Method and composition for treating osteoporosis

ABSTRACT

This invention relates to a novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) useful as inhibitors of osteoclastogenesis. The invention also provides methods of using the novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula ZOC—(CRR) m —COOH, wherein: m= 2, 3  or  4 ; Z is OH or NH 2 ; one R in the compound is from the group consisting of SO 3 H, OSO 3 H, CH 2 —SO 3 H, CH 2 —OSO 3 H, and NHSO 3 H, and the remaining Rs are H or NH 2 , for inhibition of osteoclastogenesis.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 60/512,183, filed Oct. 20, 2003, whose contents are incorporated by reference.

FIELD OF THE INVENTION

This invention relates to a novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) useful as inhibitors of osteoclastogenesis. More particularly, this invention relates to inhibitors of osteoclastogenesis containing novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula: ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in the compound is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂. Thus, the compounds may bear the general formula ZOC—CR₇R₈—CR₅R₆-CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH or ZOC—CR₃R₄—CR₁R₂—COOH wherein Z is OH or NH₂, and R₁ to R₈ denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H.

A pharmaceutical composition containing the aforementioned inhibitors of osteoclastogenesis may also contain different divalent metal ions such as Mg, Ca or Zn. The composition consists of varying amounts of the above acidic amino acid/dicarboxylic acid derivatives and their pharmaceutically acceptable selected alkali/alkaline earth metal salts. The invention also provides a process for the preparation of the aforesaid compounds, useful for the inhibition of the osteoclast differentiation, maturation and activation. These compounds can also be used for developing effective drugs for the treatment of osteoporosis, osteoarthritis, bone metastasis and bone loss in other metabolic diseases of clinical importance.

-   -   1) The inhibitors of osteoclastogenesis also contain different         divalent metal ions such as Mg, Ca or Zn, wherein all the         symbols are the same meaning as hereinafter defined and         non-toxic salts thereof as an active ingredient,     -   2) The composition consists of varying amounts of the above         acidic amino acid/dicarboxylic acid derivatives and their         pharmaceutically acceptable selected alkali/alkaline earth metal         salts, wherein all the symbols are the same meaning as         hereinafter defined and non-toxic salts thereof as an active         ingredient,     -   3) The process for the preparation of the aforesaid compounds,         useful for the inhibition of the osteoclast differentiation,         maturation and activation.     -   4) These compounds can also be used for developing effective         drugs for the treatment of osteoporosis, osteoarthritis, bone         metastasis and bone loss in other metabolic diseases of clinical         importance.

BACKGROUND OF THE INVENTION

Indian green mussels (Perna viridis) are the cheap source of proteins and considered as a delicacy. Extract prepared from green mussels by enzyme-acid hydrolysis process showed various biological activities. In our earlier patent (US patent application #20030044470) we have shown the inhibition of osteoclast differentiation and activation in the crude extract. In same continuation, attempts have been made to purify the active compound that showed inhibition of osteoclast differentiation and activation. The purification of the crude extract was done using HPLC, gel filtration and TLC methods. The purified compound was again checked for the above activity. The compound was characterized using NMR and LC-MS/MS techniques. This compound was synthesized and checked for the presence of the above biological activity. This patent in particular describes the synthesis of the compound and also its activity for inhibition of osteoclast formation.

Novel class of amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) along with calcium is for their activation to show inhibition of the osteoclastogenesis. Amino acid derivatives and calcium ion when used separately did not show any activity on inhibition of the osteoclastogenesis. The following classes of compounds are identified

-   -   (1) Natural acidic amino acids (Aspartic acid, Glutamic acid and         their amides),     -   (2) Unnatural amino acids, amides such as homoglutamic acid,     -   (3) Dicarboxylic acids such as succinic acid, glutaric acid, and         adipic acid     -   (4) N-sulfonyl, C-sulfonyl/sulfate derivatives of the above         acids     -   (5) Alkaline earth metals such as Mg, Zn and Ca as their         suitable salts.         Related Arts

A lot of information is available on the matrix metalloproteinases (MMP's) commonly used as MMP inhibitors for the treatment of osteoporosis (Nigel, R. A. Beeley, Phillip, R. J., Ansell, Andrew, J. P., Dochert, 1994, Curr. Opin. Ther. Patents., 4, 7-16). A cylinder shaped solid compound has been prepared from the atelocollagen solution, L-alanine solution and bone morphogenetic protein for treating bone loss and elevating bone deformities (Hiroo, Akhihiko, Rebecca, Wozney, Seeherman, 2003, WO Patent #2003066083). In another study glutamate and glutamate derivatives/analogs or their mixtures have been used for modulating the bone quality (Tadeusz, Jose Luis; Stefan, 2003, WO Patent # 2003043626). Toshhiro (2003) invented a compound consisting of interacting trans-activators with glutamic acid, aspartic acid and rich carboxyl-terminal domain for estrogen receptor dependent activity (Toshihiro, 2002, WO Patent # 2003000730). Glutamic acid has been defined as an effective neuromediator and one of its derivatives is involved in osteoclast formation and bone resorption. The modification of glutamic acid action in bone could be used for bone remodeling (Hopital E. Herriot, Lyon Fr., 2002, Microscopy Research and technique, 58(2), 70-76).

However, these inhibitors have various problems and efforts were made for the development of non-peptide inhibitors. For instance in the specification of EP 606046, several aryl-sulfonamide derivatives have been described. In another invention several aryl sulfonyl amino acid derivatives of the following specifications have been described (Sakaki, Kanazawa, Sugiura, Miyazaki, Ohno, 2002, U.S. Pat. No. 6,403,644) as MMP inhibitors:

-   1) N-[[4-(Benzoylamino)phenyl]sulfonyl]glycine, -   2) N-[[3-(Benzoylamino)phenyl]sulfonyl]glycine, -   3) N-[[2-(Benzoylamino)phenyl]sulfonyl]glycine, -   4) N-[[4-(Acetylamino)phenyl]sulfonyl]glycine, -   5) N-[[4-(Phenylacetylamino)phenyl]sulfonyl]glycine, -   6) N-[[4-[(Phenylethylcarbonyl)amino]phenyl]sulfonyl]glycine, -   7) N-[[4-(Cinnamoylamino)phenyl]sulfonyl]glycine, -   8) N-[[4-(N-Phenylureido)phenyl]sulfonyl]glycine, -   9) N-[[4-(N-Phenylthioureido)phenyl]sulfonyl]glycine, -   10) N-[[4-[(Benzyloxycarbonyl)amino]phenyl]sulfonyl]glycine, -   11) N-[[4-[(Phenyloxymethylcarbonyl)amino]phenyl]sulfonyl]glycine, -   12) N-[[4-[(Benzyloxymethylcarbonyl)amino]phenyl]sulfonyl]glycine, -   13) N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]glycine, -   14) N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]glycine, -   15) N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]glycine, -   16) N-[[4-(3-Nitrobenzoylamino)phenyl]sulfonyl]glycine, -   17) N-[[4-(2-Nitrobenzoylamino)phenyl]sulfonyl]glycine, -   18) N -[[4-(4-Formylbenzoylamino)phenyl]sulfonyl]glycine, -   19) N-[[4-(Benzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine, -   20) N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine, -   21)     N-[[4-(4-Methylbenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine, -   22)     N-[[4-(Methylbenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine, -   23)     N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine, -   24)     N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine, -   25)     N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine, -   26)     N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine, -   27)     N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine, -   28)     N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine, -   29) N -[(4-Pivaloyloxyphenyl)sulfonyl]-D, L-alpha-phenylglycine, -   30) N-[(4-Pivaloyloxyphenyl)sulfonyl]-D, L-phenylalanine, -   31) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]glycine, -   32) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-alanine, -   33) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-beta-alanine, -   34) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine, -   35) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-valine, -   36) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-Ieucine, -   37) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-Ieucine, -   38) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-serine, -   39)     N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-phenylalanine, -   40) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine, -   41) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-alanine     methyl ester, -   42) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine methyl     ester, -   43) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-valine     methyl ester, -   44) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-Ieucine     methyl ester, -   45) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-serine     methyl ester, -   46) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine     methyl ester, -   47) N-[[4-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid, -   48) N-[[3-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid, -   49) N-[[4-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid, -   50) N-[[3-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid, -   51) N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-glutamic acid, -   52) N-[[4-(4-Chlorobenzoylamino)phenyl]sulfonyl]-L-glutamic acid, -   53) N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-L-glutamic acid, -   54)     N-[[4-[2-(4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine     ethyl ester, -   55)     N-[[4-[2-(4-(1-Nitrophenyl)butyryloxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine     ethyl ester, -   56)     N-[[4-(2-Methoxy-2-phenylacetyloxy)phenyl]sulfonyl]-D,L-3-morpholinoalanine     ethyl ester, -   57)     N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine     ethyl ester, -   58)     N-[[3-Methyl-4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-t-butoxycarbonyl-L-lysine, -   59) N-[[4-(2-Phenylbutyryloxy)phenyl]sulfonyl]glycine, -   60)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-phenylalanine, -   61)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,     L-aspartic acid, -   62)     N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sulfonyl]-D,L-aspartic     acid, -   63)1-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonylamide]-I-cyclopropanecarboxylic     acid, -   64)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-2-(2-furanyl)glycine, -   65)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-2-(2-tri-enyl)glycine, -   66)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-L-valine, -   67)     N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-S-carboxymethyl-L-cysteine, -   68)     N-[[4-[2-Ethyl-2-(4-methoxyphenyl)butyryloxy]phenyl]sulfonyl]-glycine, -   69)     N-[[3-Methyl-4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-L-lysine, -   70) N-[[3     Methyl-4-[2-[4-(1-pyrrolidinyl)phenyl]butylyloxy]phenyl]sulfonyl]amino]pentanoic     acid, -   71) N-[[(3-Methyl-4-pivaloyloxy)phenyl]sulfonyl]-beta-alanine.     Purpose of the Invention

Bone is a metabolically active and highly organized connective tissue. The main functions of the bones are provision of mechanical and structural support, maintaining blood calcium levels, supporting haematopoiesis and housing the important vital organs such as brain, spinal cord and heart. To accomplish these functions bone needs continuous remodeling. Bone contains two distinct cell types, the osteoblasts, essential for bone formation (synthesis); and the osteoclasts, essential for bone resorption (break down). Morphogenesis and remodeling of bone involves the synthesis of bone matrix by osteoblasts and coordinated resorption by osteoclasts. The co-ordination between the osteoblasts and osteoclasts is very crucial in maintaining bone homeostasis and structural integrity of the skeleton. Both these processes are influenced by several hormones and local factors generated within bone and bone marrow, resulting in a complex network of control mechanisms. An imbalance of osteoblast and osteoclast functions can result in skeletal abnormalities characterized by increased or decreased bone mass. This may leads to excessive bone loss that reflects the balance of bone formation and bone resorption. Bone destruction or resorption is carried out by haematopoietically derived osteoclasts. Their number and activity is determined by cell lineage allocation, proliferation and differentiation of osteoclast precursors and the resorptive efficiency of mature osteoclasts. Important bone diseases such as osteoporosis, rheumatoid arthritis, Paget's disease of bone and bone metastasis of breast and prostate cancers are caused by increased osteoclast activity (Teitelbaum, 2000). In these disorders bone resorption exceeds bone formation resulting in decreased skeletal mass. This causes bones to become thin, fragile and susceptible to fracture. The consequences of osteoporotic bone fractures include chronic pain in bone, body deformity including height loss and muscle weakness. Therefore, to understand both pathogenesis and successful treatment of these bone diseases there is a need for better understanding of biology of osteoclasts.

Osteoporosis is now a serious problem that imposes substantial limitations on the affected individuals. In human, 1 in 3 women and 1 in 12 men over 45 years are at risk of suffering painful and deforming fractures as a result of osteoporosis. More women die after hip fractures than from cancers of ovaries, cervix and uterus. Osteoporosis occurs at a relatively earlier age in Indian males and females compared to western countries (Gupta, 1996). A variety of disadvantages are associated with current therapeutic agents used in osteoporosis and other metabolic bone disorders. The side effects of current therapies include increase in the risk of breast and uterine cancers, upper gastrointestinal distress and induction of immune responses. Drugs that inhibit the formation or activity of osteoclasts and with no toxicity and harmful side effects will be valuable for treating osteoporosis and other bone diseases.

Bone resorption and loss of calcium from bone are complications associated with arthritis, many cancers and with bone metastases of breast and prostate tumors. Because of lack of research into osteoporosis and related diseases, we don't know all the answers to treat these diseases. Progress in better understanding the pathogenesis and successful treatment of these diseases to date has targeted osteoclast.

Osteoclasts, the only cells capable of resorbing bone differentiate from the haemopoietic precursors of monocyte/macrophage lineage that also give rise to macrophages and dendritic cells (Miyamoto et al. 2001). Lineage choice and the differentiation process is guided by lineage restricted key regulatory molecules and transcription factors. Osteoclasts are large multinucleated cells. They are formed by the fusion of mononuclear cells of haemopoietic origin and not by mitosis, since DNA synthesis is not required. Osteoclast formation and bone resorption is regulated by many hormones, growth factors and immune cell-derived cytokines (Udagawa et al. 1995, Wani et al. 1999, Fox et al. 2000, Fuller et al. 2000). These factors act directly or indirectly via other cell types to influence osteoclast differentiation. The most important cell type influencing osteoclast formation is osteoblast, which promote this process by a contact-dependent mechanism. Recent advances revealed that two molecules, macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) expressed by osteoblasts are essential and sufficient for the differentiation of haemopoietic cells to form osteoclasts (Tanaka et al. 1993, Anderson et al., 1997, Wong et al. 1997, Lacey et al. 1998, Yasuda et al. 1998). The precise role of other cells, such as T lymphocytes in bone homeostasis is yet to be fully elucidated. It has recently been reported that activated T cells regulates osteoclast formation by some unknown mechanisms. T cells support osteoclast formation by RANKL-dependent and RANKL-independent mechanisms (Weitzmann et al. 2001). Cytokines produced by activated T cells, as well as by other cell types regulates osteoclastogenesis in physiological and pathological conditions. Recent discovery of RANKL has enabled us for the meticulous dissection of mechanisms by which various factors regulate osteoclastogenesis, and better understanding of both pathogenesis and successful treatment bone diseases. In our preliminary studies, we have investigated the role of novel compounds on osteoclastogenesis induced by RANKL in the presence of M-CSF in stromal cell-free cultures of osteoclast precursors.

Natural products from plants and organisms have frequently been used as a source for development of effective drugs. There is an increased interest in analysis of natural products from marine organisms. Sea animals contain metabolites which can be used for treatment of many diseases.

The inventors have previously shown (U.S. Pat. No. 2,003,066083) that a novel extract (mussel hydrolysate) prepared from the Indian green mussel (Perna viridis) inhibits the osteoclast differentiation in murine haemopoietic precursors of monocyte/macrophage cell lineage. The extract also inhibits the bone resorbing activity of osteoclasts. There was approximately 80-90% inhibition of osteoclast formation and bone resorption in the presence of extract. More importantly, the extract is non-toxic to other cells and is useful to prepare a drug for the treatment of osteoporosis and other bone diseases.

In further investigation, at each stages of purification we found a significant inhibition of osteoclast formation and bone resorption (60-90%). We have purified some active components from extract and these active components significantly inhibit both osteoclast formation and bone resorption. These active compounds can be used in therapeutic settings to protect and cure the individuals against osteoporosis and other metabolic bone diseases.

The current known therapeutic agents have a variety of associated disadvantages. The side effects of current therapies include an elevated risk of breast and uterine cancers, upper gastrointestinal distress and induction of immune responses (Watts' 1999). Our earlier US Patent (#2003066083) describes preparation of mussell hydrolysate from the Indian green mussel (Perna viridis) and its inhibition of the osteoclast differentiation in murine hemopoietic precursors of monocyte/macrophage cell lineage. The extract also shows inhibition of the bone resorbing activity of osteoclasts.

The present inventors have found that a series of novel sulfonic acid/sulfate derivatives of acidic amino acids, aspartic acids, glutamic acid, homoglutamic acid and their related aliphatic dicarboxylic acids (Succinic acid, glutaric acid and adipic acid) have inhibitory activity against osteoclast formation and bone resorption. These compounds are novel and non-toxic to other cells. The active compounds may play a vital role in inhibition of differentiation of osteoclast from hemopoietic precursors and can be used in therapeutic settings to protect and cure the individuals against osteoporosis and other metabolic bone diseases.

SUMMARY OF THE INVENTION

This invention relates to a novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) useful as inhibitors of osteoclastogenesis. The invention also provides methods of using the novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in the composition is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂. Thus, the compounds may bear the general formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH or ZOC—CR₃R₄—CR₁R₂—COOH wherein Z is OH or NH₂, and R₁ to R₈ denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H. Mixtures of these compounds may be administered, as well.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to:

-   A) Osteoclast inhibitors containing novel class of acidic amino     acid/dicarboxylic acid derivatives (sulfonic acid/sulfate     derivatives of naturally occurring amino acids and their amides); -   B) Osteoclast inhibitors containing novel class of acidic amino     acid/dicarboxylic acid derivatives of the general formula     ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in     the composition is from the group consisting of SO₃H, OSO₃H,     CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂.     Thus, compounds may bear the general formula:     ZOC—CR₃R₄—CR₁R₂—COOH  (Ia)     ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH  (Ib)     ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH  (Ic)     wherein:

Z is OH or NH₂; and

R₁ to R₈ are H, NH₂, SO₃H or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H. And this includes the following class of compounds:

-   -   1. A compound in which Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═H is the same         meaning as hereinbefore defined;     -   2. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   3. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   4. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═SO₃H is the         same meaning as hereinbefore defined;     -   5. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the         same meaning as hereinbefore defined;     -   6. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═SO₃H is the         same meaning as hereinbefore defined;     -   7. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═OSO₃H is the         same meaning as hereinbefore defined;     -   8. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂SO₃H is the same         meaning as hereinbefore defined;     -   9. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂OSO₃H is the same         meaning as hereinbefore defined;     -   10. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═SO₃H is the same         meaning as hereinbefore defined;     -   11. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═OSO₃H is the same         meaning as hereinbefore defined;     -   12. A compound in which Z═OH, R₂═NHSO₃H, R₁═R₃═R₄═H is the same         meaning as hereinbefore defined;     -   13. A compound in which Z═OH, R₂═H, R₁═CH₂SO₃H is the same         meaning as hereinbefore defined;     -   14. A compound in which Z═OH, R₂═H, R₁═CH₂OSO₃H is the same         meaning as hereinbefore defined;     -   15. A compound in which Z═OH, R₂═H, R₁═SO₃H is the same meaning         as hereinbefore defined;     -   16. A compound in which Z═OH, R₂═H, R₁═OSO₃H is the same meaning         as hereinbefore defined;     -   17. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the         same meaning as hereinbefore defined;     -   18. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the         same meaning as hereinbefore defined;     -   19. A compound in which Z═OH, R₂═NH₂, R₁═R₄═H, R₃═SO₃H is the         same meaning as hereinbefore defined;     -   20. A compound in which Z═OH, R₂═NH₂, R═R₄═H, R₃═OSO₃H is the         same meaning as hereinbefore defined;     -   21. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₄═SO₃H is the         same meaning as hereinbefore defined;     -   22. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₄═OSO₃H is the         same meaning as hereinbefore defined;     -   23. A compound in which R₁═NHSO₃H, R₂═R₃═R₄═H is the same         meaning as hereinbefore defined;     -   24. A compound in which Z═NH₂, R₁═H, R₂═CH₂SO₃H is the same         meaning as hereinbefore defined;     -   25. A compound in which Z═NH₂, R₁═H, R₂═CH₂OSO₃H is the same         meaning as hereinbefore defined;     -   26. A compound in which Z═NH₂, R₁═H, R₂═SO₃H is the same meaning         as hereinbefore defined;     -   27. A compound in which Z═NH₂, R₁═H, R₂═OSO₃H is the same         meaning as hereinbefore defined;     -   28. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₂═SO₃H is the same         meaning as hereinbefore defined;     -   29. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the same         meaning as hereinbefore defined;     -   30. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═SO₃H is the same         meaning as hereinbefore defined;     -   31. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the same         meaning as hereinbefore defined;     -   32. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₄═SO₃H is the same         meaning as hereinbefore defined;     -   33. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₄═OSO₃H is the same         meaning as hereinbefore defined;     -   34. A compound in which Z═NH₂, R₂═NHSO₃H, R₁═R₃═R₄═H is the same         meaning as hereinbefore defined;     -   35. A compound in which Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   36. A compound in which Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   37. A compound in which Z═OH, R₂ to R₄═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   38. A compound in which Z═OH, R₂ to R₄═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   39. A compound in which Z═R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   40. A compound in which Z═R₂═NH₂, R₃═R₄═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   41. A compound in which Z═R₂═NH₂, R₁═R₄═H, R₃═SO₃H is the same         meaning as hereinbefore defined;     -   42. A compound in which Z═R₂═NH₂, R₁═R₄═H, R₃═OSO₃H is the same         meaning as hereinbefore defined;     -   43. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₄═SO₃H is the same         meaning as hereinbefore defined;     -   44. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₄═OSO₃H is the same         meaning as hereinbefore defined;     -   45. A compound in which Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═R₅═R₆═H is the         same meaning as hereinbefore defined;     -   46. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   47. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H is the         same meaning as hereinbefore defined;     -   48. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   49. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   50. A compound in which Z═OH, R₂ to R₆═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   51. A compound in which Z═OH, R₂ to R₆═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   52. A compound in which Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   53. A compound in which Z═OH, R₁═NH₂, R₃ to &═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   54. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═SO₃H         is the same meaning as hereinbefore defined;     -   55. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═OSO₃H         is the same meaning as hereinbefore defined;     -   56. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H is         the same meaning as hereinbefore defined;     -   57. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H is         same meaning as hereinbefore defined;     -   58. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H is         the same meaning as hereinbefore defined;     -   59. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H is         the same meaning as hereinbefore defined;     -   60. A compound in which Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═SO₃H is the         same meaning as hereinbefore defined;     -   61. A compound in which Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H is         the same meaning as hereinbefore defined;     -   62. A compound in which Z═OH, R₂═NHSO₃H, R₁, R₃ to R₆═H is the         same meaning as hereinbefore defined;     -   63. A compound in which Z═OH, R₂ to R₆═H, R₁═CH₂SO₃H is the same         meaning as hereinbefore defined;     -   64. A compound in which Z═OH, R₂ to R₆═H, R₁═CH₂OSO₃H is the         same meaning as hereinbefore defined;     -   65. A compound in which Z═OH, R₂═NH₂, R₃ to R₆H, R₁═SO₃H is the         same meaning as hereinbefore defined;     -   66. A compound in which Z═OH, R₂═NH₂, R₃ to R₆H, R₁═OSO₃H is the         same meaning as hereinbefore defined;     -   67. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H is         the same meaning as hereinbefore defined;     -   68. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H is         the same meaning as hereinbefore defined;     -   69. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H is         the same meaning as hereinbefore defined;     -   70. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H is         the same meaning as hereinbefore defined;     -   71. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H is         the same meaning as hereinbefore defined;     -   72. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H is         the same meaning as hereinbefore defined;     -   73. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H is         the same meaning as hereinbefore defined;     -   74. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H is         the same meaning as hereinbefore defined;     -   75. A compound in which Z═NH₂, R₁═NHSO₃H, R₂ to R₆═H is the same         meaning as hereinbefore defined;     -   76. A compound in which Z═R₁═NH₂, R₃ to R₆═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   77. A compound in which Z═R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   78. A compound in which Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═SO₃H is         the same meaning as hereinbefore defined;     -   79. A compound in which Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═OSO₃H is         the same meaning as hereinbefore defined;     -   80. A compound in which Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H is the         same meaning as hereinbefore defined;     -   81. A compound in which Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H is the         same meaning as hereinbefore defined;     -   82. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H is the         same meaning as hereinbefore defined;     -   83. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H is the         same meaning as hereinbefore defined;     -   84. A compound in which Z═R₁═NH₂, R₂ to R₅═H, R₆═SO₃H is the         same meaning as hereinbefore defined;     -   85. A compound in which Z═R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H is the         same meaning as hereinbefore defined;     -   86. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   87. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H is         the same meaning as hereinbefore defined;     -   88. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   89. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   90. A compound in which Z═NH₂, R₂ to R₆═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   91. A compound in which Z═NH₂, R₂ to R₆═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   92. A compound in which Z═NH₂, R₂═NHSO₃H; R₁═H, R₃ to R₆═H is         the same meaning as hereinbefore defined;     -   93. A compound in which Z═NH₂, R₂ to R₆═H, R₁═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   94. A compound in which Z═NH₂, R₂ to R₆═H, R₁═CH₂OSO₃H is the         same meaning as hereinbefore defined;     -   95. A compound in which Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═SO₃H is         the same meaning as hereinbefore defined;     -   96. A compound in which Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═OSO₃H is         the same meaning as hereinbefore defined;     -   97. A compound in which Z═NH₂, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H is         the same meaning as hereinbefore defined;     -   98. A compound in which Z═R₂═NH₂, R₁, R₄ to & H, R₃═OSO₃H is the         same meaning as hereinbefore defined;     -   99. A compound in which Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H is the         same meaning as hereinbefore defined;

-   100. A compound in which Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H is the     same meaning as hereinbefore defined;     -   101. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H is the         same meaning as hereinbefore defined;     -   102. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H is         the same meaning as hereinbefore defined;     -   103. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H is the         same meaning as hereinbefore defined;     -   104. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H is         the same meaning as hereinbefore defined;     -   105. A compound in which Z═OH, R₁═NHSO₃H, R₂ to R₈═H is the same         meaning as hereinbefore defined;     -   106. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   107. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═CH₂OSO₃H is         the same meaning as hereinbefore defined;     -   108. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   109. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   110. A compound in which Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═SO₃H is         the same meaning as hereinbefore defined;     -   111. A compound in which Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H is         the same meaning as hereinbefore defined;     -   112. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H         is the same meaning as hereinbefore defined;     -   113. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H,         R₃═OSO₃H is the same meaning as hereinbefore defined;     -   114. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H,         R₄═SO₃H is the same meaning as hereinbefore defined;     -   115. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H,         R₄═OSO₃H is the same meaning as hereinbefore defined;     -   116. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H is the same meaning as hereinbefore defined;     -   117. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H is the same meaning as hereinbefore defined;     -   118. A compound in which Z═OH, R₁ ═N—H₂, R₂═R₅═H, R₇═R₈═H,         R₆═SO₃H the same meaning as hereinbefore defined;     -   119. A compound in which Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H,         R₆═OSO₃H is the same meaning as hereinbefore defined;     -   120. A compound in which Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H         is the same meaning as is before defined;     -   121. A compound in which Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H,         R₇═OSO₃H is the same meaning as hereinbefore defined;     -   122. A compound in which Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═SO₃H is         the same meaning as hereinbefore defined;     -   123. A compound in which Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H is         the same meaning as hereinbefore defined;     -   124. A compound in which Z═OH, R₂═NHSO₃H, R₁, R₃ to R₈═H is the         same meaning as hereinbefore defined;     -   125. A compound in which Z═OH, R₂ to R₈═H, R₁═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   126. A compound in which Z═OH, R₂ to R₈═H, R₁═CH₂OSO₃H is the         same meaning as hereinbefore defined;     -   127. A compound in which Z═OH, R₂ to R₈═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   128. A compound in which Z═OH, R₂ to R₈═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   129. A compound in which Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═SO₃H is         the same meaning as hereinbefore defined;     -   130. A compound in which Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H is         the same meaning as hereinbefore defined;     -   131. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H         is the same meaning as hereinbefore defined;     -   132. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H         is the same meaning as hereinbefore defined;     -   133. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H,         R₄═SO₃H is the same meaning as hereinbefore defined;     -   134. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H,         R₄═OSO₃H is the same meaning as hereinbefore defined;     -   135. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H is the same meaning as is before defined;     -   136. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H is the same meaning as hereinbefore defined;     -   137. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H,         R₇═R₈═H, R₆═SO₃H is the same meaning as hereinbefore defined;     -   138. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H,         R₇═R₈═H, R₆═OSO₃H is the same meaning as hereinbefore defined;     -   139. A compound in which Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H,         R₇═SO₃H the same meaning as hereinbefore defined;     -   140. A compound in which Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H,         R₇═OSO₃ is the same meaning as hereinbefore defined;     -   141. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H         is the same meaning as hereinbefore defined;     -   142. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H,         R₈═OSO₃H is the same meaning as hereinbefore defined;     -   143. A compound in which Z═NH₂, R₁═NHSO₃H, R₂ to R₈═H is the         same meaning as hereinbefore defined;     -   144. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂SO₃H is         the same meaning as hereinbefore defined;     -   145. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂OSO₃H         is the same meaning as hereinbefore defined;     -   146. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═SO₃H is         the same meaning as hereinbefore defined;     -   147. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═OSO₃H is         the same meaning as hereinbefore defined;     -   148. A compound in which Z═R₁═NH₂, R₃ to R₈═H, R₂═SO₃H is the         same meaning as hereinbefore defined;     -   149. A compound in which Z═R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H is the         same meaning as hereinbefore defined;     -   150. A compound in which Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H is         the same meaning as hereinbefore defined;     -   151. A compound in which Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H is         the same meaning as hereinbefore defined;     -   152. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H         is the same meaning as hereinbefore defined;     -   153. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H         is the same meaning as hereinbefore defined;     -   154. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H is the same meaning as hereinbefore defined;     -   155. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H is the same meaning as hereinbefore defined;     -   156. A compound in which Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H is         the same meaning as hereinbefore defined;     -   157. A compound in which Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H is         the same meaning as hereinbefore defined;     -   158. A compound in which Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H is         the same meaning as hereinbefore defined;     -   159. A compound in which Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H is         the same meaning as hereinbefore defined;     -   160. A compound in which Z═R₁═NH₂, R₂ to R₇═H, R₈═SO₃H is the         same meaning as hereinbefore defined;     -   161. A compound in which Z═R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H is the         same meaning as hereinbefore defined;     -   162. A compound in which Z═NH₂, R₂═NHSO₃H, R₁ and R₃ to R₈═H is         the same meaning as hereinbefore defined;     -   163. A compound in which Z═NH₂, R₂ to R₈═H, R₁═CH₂SO₃H is the         same meaning as hereinbefore defined;     -   164. A compound in which Z═NH₂, R₂ to R₈═H, R₁═CH₂OSO₃H is the         same meaning as hereinbefore defined;     -   165. A compound in which Z═NH₂, R₂ to R₈═H, R₁═SO₃H is the same         meaning as hereinbefore defined;     -   166. A compound in which Z═NH₂, R₂ to R₈═H, R₁═OSO₃H is the same         meaning as hereinbefore defined;     -   167. A compound in which Z═R₂═NH₂, R₃ to R₈═H, R₁═SO₃H is the         same meaning as hereinbefore defined;     -   168. A compound in which Z═R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H is the         same meaning as hereinbefore defined;     -   169. A compound in which Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H is         the same meaning as hereinbefore defined;     -   170. A compound in which Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H is         the same meaning as hereinbefore defined;     -   171. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H         is the same meaning as hereinbefore defined;     -   172. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H         is the same meaning as hereinbefore defined;     -   173. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H is the same meaning as hereinbefore defined;     -   174. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H is the same meaning as hereinbefore defined;     -   175. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═SO₃H is the same meaning as hereinbefore defined;     -   176. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═OSO₃H is the same meaning as hereinbefore defined;     -   177. A compound in which Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═SO₃H         is the same meaning as hereinbefore defined;     -   178. A compound in which Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H         is the same meaning as hereinbefore defined;     -   179. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H is         the same meaning as hereinbefore defined;     -   180. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H is         the same meaning as hereinbefore defined.         C) The osteoclast inhibitors also contained different divalent         metal ions such as Mg, Ca and Zn. The composition consisted of         varying amounts of the above acid amino acid/dicarboxylic acid         derivatives and their pharmaceutically acceptable salts. Non         toxic salts of the present invention are contained all         pharmaceutically acceptable salts, for example, general salts,         acid addition salt, hydrate salts.

The compounds of the formulae (Ia), (lb) and (Ic) of the present invention may be converted into the corresponding salts. Non toxic and water soluble salts are preferable. Suitable salts for example are as follows:

-   -   Salts of alkaline earth metals (Mg, Ca etc)     -   Ammonium Salts     -   Salts of pharmaceutically acceptable organic amines (tetramethyl         ammonium, triethyl amine, methyl amine, cyclopentyl amine,         benzylamine, phenethylamine, piperidine, monoethanolamine,         diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,         N-methyl glucamine, etc.         d) In the compound of the present invention of the formulae         (Ia), (lb) and (Ic) the following non toxic derivatives thereof         are preferable:     -   1. L-Aspartic acid, N-Sulfonic acid     -   2. L-Aspartic acid, 2β-sulfonic acid     -   3. L-Aspartic acid, 2β-sulfate     -   4. L-aspartic acid, 3α-sulfonic acid     -   5. L-aspartic acid, 3α-sulfate     -   6. L-aspartic acid, 3β-sulfonic acid     -   7. L-aspartic acid, 3β-sulfate     -   8. 2α,3-dicarboxy, propane-1-sulfonic acid     -   9. 2α,3-dicarboxy, propane-1-sulfate     -   10. 1α,2-carboxy ethane sulfonic acid     -   11. 1α,2-carboxy ethane sulfate     -   12. D-aspartic acid, N-sulfonic acid     -   13. 2β,3-carboxy, propane-1-sulfonic acid     -   14. 2β,3-carboxy, propane-1-sulfate     -   15. 1β,2-carboxy ethane-1-sulfonic acid     -   16. 1β,2-carboxy ethane-1-sulfate     -   17. D-aspartic acid, 2α-sulfonic acid     -   18. D-aspartic acid, 2α-sulfonic acid     -   19. D-Aspartic acid, 3α-sulfonic acid     -   20. D-Aspartic acid, 3α-sulfate     -   21. D-Aspartic acid, 3β-sulfonic acid     -   22. D-aspartic acid, 3β-sulfate     -   23. L-asparagine, N-sulfonic acid     -   24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   25. 2α-carboxy, 3-carboxamido, propane-1-sulfate     -   26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid     -   27. 1α-carboxy, 2-carboxamido, ethane sulfate     -   28. L-asparagine, 2β-sulfonic acid     -   29. -asparagine, 2β-sulfate     -   30. L-asparagine, 3α-sulfonic acid     -   31. L-asparagine, 3α-sulfate     -   32. L-asparagine, 3β-sulfonic acid     -   33. L-asparagine, 3β-sulfate     -   34. D-asparagine, N-sulfonic acid     -   35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   36. 2β-carboxy, 3-carboxamido, propane-1-sulfate     -   37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid     -   38. 1β-carboxy, 2-carboxamido, ethane sulfate     -   39. D-asparagine, 2α-sulfonic acid     -   40. D-asparagine, 2α-sulfate     -   41. D-asparagine, 3α-sulfonic acid     -   42. D-asparagine, 3α-sulfate     -   43. D-asparagine, 3β-sulfonic acid     -   44. D-asparagine, 3β-sulfate     -   45. L-glutamic acid, N-sulfonic acid     -   46. 2α,4-dicarboxy, butane-1-sulfonic acid     -   47. 2α,4-dicarboxy, butane-1-sulfate     -   48. 1α,3-dicarboxy, propane sulfonic acid     -   49. 1α,3-dicarboxy, propane sulfate     -   50. 1β,3-dicarboxy, propane sulfate     -   51. 1β,3-dicarboxy, propane sulfonic acid     -   52. L-glutamic acid, 2β-sulfonic acid     -   53. L-glutamic acid, 2β-sulfate     -   54. L-glutamic acid, 3α-sulfonic acid     -   55. L-glutamic acid, 3α-sulfate     -   56. L-glutamic acid, 3β-sulfonic acid     -   57. L-glutamic acid, 3β-sulfate     -   58. L-glutamic acid, 4α-sulfonic acid     -   59. L-glutamic acid, 4α-sulfate     -   60. L-glutamic acid, 4β-sulfonic acid     -   61. L-glutamic acid, 4β-sulfate     -   62. D-glutamic acid, N-sulfonic acid     -   63. 2β,4-dicarboxy, butane-1-sulfonic acid     -   64. 2β,4-dicarboxy, butane-1-sulfate     -   65. D-glutamic acid, 2α-sulfonic acid     -   66. D-glutamic acid, 2α-sulfate     -   67. D-glutamic acid, 3α-sulfonic acid     -   68. D-glutamic acid, 3α-sulfate     -   69. D-glutamic acid, 3β-sulfonic acid     -   70. D-glutamic acid, 3β-sulfate     -   71. D-glutamic acid, 4α-sulfonic acid     -   72. D-glutamic acid, 4α-sulfate     -   73. D-glutamic acid, 4β-sulfonic acid     -   74. D-glutamic acid, 4β-sulfate     -   75. L-glutamine, N-sulfonic acid     -   76. L-glutamine, 2β-sulfonic acid     -   77. L-glutamine, 2β-sulfate     -   78. L-glutamine, 3α-sulfonic acid     -   79. L-glutamine, 3α-sulfate     -   80. L-glutamine, 3β-sulfonic acid     -   81. L-glutamine, 3β-sulfate     -   82. L-glutamine, 4α-sulfonic acid     -   83. L-glutamine, 4α-sulfate     -   84. L-glutamine, 4β-sulfonic acid     -   85. L-glutamine, 4β-sulfate     -   86. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid     -   87. 2α-carboxy, 4-carboxamido, butane-1-sulfate     -   88. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   89. 1α-carboxy, 3-carboxamido, propane-1-sulfate     -   90. 1β-carboxy, 3-carboxamido, propane-1-sulfate     -   91. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   92. D-glutamine, N-sulfonic acid     -   93. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid     -   94. 2β-carboxy, 4-carboxamido, butane-1-sulfate     -   95. D-glutamine, 2α-sulfonic acid     -   96. D-glutamine, 2α-sulfate     -   97. D-glutamine, 3α-sulfonic acid     -   98. D-glutamine, 3α-sulfate     -   99. D-glutamine, 3β-sulfonic acid     -   100. D-glutamine, 3β-sulfate     -   101. D-glutamine, 4α-sulfonic acid     -   102. D-glutamine, 4α-sulfate     -   103. D-glutamine, 4β-sulfonic acid     -   104. D-glutamine, 4β-sulfate     -   105. L-homoglutamic acid, N-sulfonic acid     -   106. Pentane-2α,5-dicarboxy-1-sulfonic acid     -   107. Pentane-2α,5-dicarboxy-1-sulfate     -   108. Butane-1α,4-dicarboxy-1-sulfonic acid     -   109. Butane-1α,4-dicarboxy-1-sulfate     -   110. L-homoglutamic acid, 2β-sulfonic acid     -   111. L-homoglutamic acid, 2β-sulfate     -   112. L-homoglutamic acid, 3α-sulfonic acid     -   113. L-homoglutamic acid, 3α-sulfate     -   114. L-homoglutamic acid, 3β-sulfonic acid     -   115. L-homoglutamic acid, 3β-sulfate     -   116. L-homoglutamic acid, 4α-sulfonic acid     -   117. L-homoglutamic acid, 4α-sulfate     -   118. L-homoglutamic acid, 4β-sulfonic acid     -   119. L-homoglutamic acid, 4β-sulfate     -   120. L-homoglutamic acid, 5α-sulfonic acid     -   121. L-homoglutamic acid, 5α-sulfate     -   122. L-homoglutamic acid, 5β-sulfonic acid     -   123. L-homoglutamic acid, 5β-sulfate     -   124. D-homoglutamic acid, N-sulfonic acid     -   125. Pentane-2β, 5-dicarboxy-1-sulfonic acid     -   126. Pentane-2β, 5-dicarboxy-1-sulfate     -   127. Butane-1β, 4-dicarboxy-1-sulfonic acid     -   128. Butane-1β, 4-dicarboxy-1-sulfate     -   129. D-homoglutamic acid, 2α-sulfonic acid     -   130. D-homoglutamic acid, 2α-sulfate     -   131. D-homoglutamic acid, 3α-sulfonic acid     -   132. D-homoglutamic acid, 3α-sulfate     -   133. D-homoglutamic acid, 3β-sulfonic acid     -   134. D-homoglutamic acid, 3β-sulfate     -   135. D-homoglutamic acid, 4α-sulfonic acid     -   136. D-homoglutamic acid, 4α-sulfate     -   137. D-homoglutamic acid, 4β-sulfonic acid     -   138. D-homoglutamic acid, 4β-sulfate     -   139. D-homoglutamic acid, 5α-sulfonic acid     -   140. D-homoglutamic acid, 5α-sulfate     -   141. D-homoglutamic acid, 5β-sulfonic acid     -   142. D-homoglutamic acid, 5β-sulfate     -   143. L-homoglutamine, N-sulfonic acid     -   144. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid     -   145. Pentane-2α-carboxy, 5-carboxamido-1-sulfate     -   146. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid     -   147. Butane-1α-carboxy, 4-carboxamido-1-sulfate     -   148. L-homoglutamine, 2β-sulfonic acid     -   149. L-homoglutamine, 2β-sulfate     -   150. L-homoglutamine, 3α-sulfonic acid     -   151. L-homoglutamine, 3α-sulfate     -   152. L-homoglutamine, 3β-sulfonic acid     -   153. L-homoglutamine, 3β-sulfate     -   154. L-homoglutamine, 4α-sulfonic acid     -   155. L-homoglutamine, 4α-sulfate     -   156. L-homoglutamine, 4β-sulfonic acid     -   157. L-homoglutamine, 4β-sulfate     -   158. L-homoglutamine, 5α-sulfonic acid     -   159. L-homoglutamine, 5α-sulfate     -   160. L-homoglutamine, 5β-sulfonic acid     -   161. L-homoglutamine, 5β-sulfate     -   162. D-homoglutamine, N-sulfonic acid     -   163. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid     -   164. Pentane-2β-carboxy, 5-carboxamido-1-sulfate     -   165. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid     -   166. Butane-1β-carboxy, 4-carboxamido-1-sulfate     -   167. D-homoglutamine, 2α-sulfonic acid     -   168. D-homoglutamine, 2α-sulfate     -   169. D-homoglutamine, 3α-sulfonic acid     -   170. D-homoglutamine, 3α-sulfate     -   171. D-homoglutamine, 3β-sulfonic acid     -   172. D-homoglutamine, 3β-sulfate     -   173. D-homoglutamine, 4α-sulfonic acid     -   174. D-homoglutamine, 4α-sulfate     -   175. D-homoglutamine, 4β-sulfonic acid     -   176. D-homoglutamine, 4β-sulfate     -   177. D-homoglutamine, 5α-sulfonic acid     -   178. D-homoglutamine, 5α-sulfate     -   179. D-homoglutamine, 5β-sulfonic acid     -   180. D-homoglutamine, 5β-sulfate.         e) a process for the preparation of sulfonic acid/sulfate         derivatives of the formula (Ia) and non-toxic salts thereof:     -   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═H;     -   2. A compound wherein Z═OH, R₁═NH₂, R₃═R₄═H, R₂═SO₃H;     -   3. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═OSO₃H;     -   4. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═SO₃H;     -   5. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;     -   6. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═SO₃H;     -   7. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═OSO₃H;     -   8. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂SO₃H;     -   9. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂OSO₃H;     -   10. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═SO₃H;     -   11. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═OSO₃H;     -   12. A compound in which Z═OH, R₂═NHSO₃H, R₁═R₃═R₄═H;     -   13. A compound in which Z═OH, R₂═H, R₁═CH₂SO₃H;     -   14. A compound in which Z═OH, R₂═H, R₁═CH₂OSO₃H;     -   15. A compound in which Z═OH, R₂═H, R₁═SO₃H;     -   16. A compound in which Z═OH, R₂═H, R₁═OSO₃H;     -   17. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H;     -   18. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H;     -   19. A compound in which Z═OH, R₂═NH₂, R₁═R₄═H, R₃═SO₃H;     -   20. A compound wherein Z═OH, R₂═NH₂, R═R₄═H, R₃═OSO₃H;     -   21. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₄═SO₃H;     -   22. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₄═OSO₃H;     -   23. A compound wherein R₁═NHSO₃H, R₂═R₃═R₄═H;     -   24. A compound wherein Z═NH₂, R₁═H, R₂═CH₂SO₃H;     -   25. A compound wherein Z═NH₂, R₁═H, R₂═CH₂OSO₃H;     -   26. A compound wherein Z═NH₂, R₁═H, R₂═SO₃H;     -   27. A compound wherein Z═NH₂, R₁═H, R₂═OSO₃H;     -   28. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₂═SO₃H;     -   29. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;     -   30. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═SO₃H;     -   31. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;     -   32. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₄═SO₃H;     -   33. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₄═OSO₃H;     -   34. A compound wherein Z═NH₂, R₂═NHSO₃H, R₁═R₃═R₄═H;     -   35. A compound wherein Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H;     -   36. A compound wherein Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H;     -   37. A compound wherein Z═OH, R₂ to R₄═H, R₁═SO₃H;     -   38. A compound wherein Z═OH, R₂ to R₄═H, R₁═OSO₃H;     -   39. A compound wherein Z═R₂═NH₂, R₃═R₄═H, R₁═SO₃H;     -   40. A compound wherein Z═R₂═NH₂, R₃═R₄═H, R₁═OSO₃H;     -   41. A compound wherein Z═R₂═NH₂, R₁═R₄═H, R₃═SO₃H;     -   42. A compound wherein Z═R₂═NH₂, R₁═R₄═H, R₃═OSO₃H;     -   43. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₄═SO₃H;     -   44. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₄═OSO₃H;         f) a process for the preparation of sulfonic acid/sulfate         derivatives of the formula (Ib) and non-toxic salts thereof:     -   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═R₅═R₆═H;     -   2. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═CH₂SO₃H;     -   3. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H;     -   4. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═SO₃H;     -   5. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═OSO₃H;

-   6. A compound wherein Z═OH, R₂ to R₆═H, R₁═OSO₃H;

-   7. A compound wherein Z═OH, R₂ to R₆═H, R₁═SO₃H;

-   8. A compound wherein Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═SO₃H;

-   9. A compound wherein Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H;     -   10. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═SO₃H;     -   11. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═OSO₃H;     -   12. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H;     -   13. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H;     -   14. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H;     -   15. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H;     -   16. A compound wherein Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═SO₃H;     -   17. A compound wherein Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H;     -   18. A compound wherein Z═OH, R₂═NHSO₃H, R₁, R₃ to R₆═H;     -   19. A compound wherein Z═OH, R₂ to R₆═H, R₁═CH₂SO₃H;     -   20. A compound wherein Z═OH, R₂ to R₆═H, R₁═CH₂OSO₃H;

-   21. A compound wherein Z═OH, R₂═NH₂, R₃ to R₆H, R₁═SO₃H;     -   22. A compound wherein Z═OH, R₂═NH₂, R₃ to R₆H, R₁═OSO₃H;     -   23. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H;     -   24. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H;     -   25. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H;     -   26. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H;     -   27. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H;     -   28. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H;     -   29. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, &═SO₃H;     -   30. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H;     -   31. A compound wherein Z═NH₂, R₁═NHSO₃H, R₂ to R₆═H;     -   32. A compound wherein Z═R₁═NH₂, R₃ to R₆═H, R₂═SO₃H;     -   33. A compound wherein Z═R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H;     -   34. A compound wherein Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═SO₃H;     -   35. A compound wherein Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═OSO₃H;     -   36. A compound wherein Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H;     -   37. A compound wherein Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H;     -   38. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H;     -   39. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H;     -   40. A compound wherein Z═R₁═NH₂, R₂ to R₅═H, R₆═SO₃H;     -   41. A compound wherein Z═R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H;     -   42. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂SO₃H;     -   43. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H;     -   44. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═SO₃H;     -   45. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═OSO₃H;     -   46. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═OSO₃H;     -   47. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═SO₃H;     -   48. A compound wherein Z═NH₂, R₂═NHSO₃H; R₁═H, R₃ to R₆═H;     -   49. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═CH₂SO₃H;     -   50. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═CH₂OSO₃H;     -   51. A compound wherein Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═SO₃H;     -   52. A compound wherein Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═OSO₃H;     -   53. A compound wherein Z═NH₂, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H;     -   54. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H;     -   55. A compound wherein Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H;     -   56. A compound wherein Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H;     -   57. A compound wherein Z═R₂═NH₂, R₁═R₃═P4═R₆═H, R₅═SO₃H;     -   58. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H;     -   59. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H;     -   60. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H;         g) a process for the preparation of sulfonic acid/sulfate         derivatives of the formula (Ic) and non-toxic salts thereof:     -   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂ to R₈═H;     -   2. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═CH₂SO₃H;     -   3. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═CH₂OSO₃H;     -   4. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═SO₃H;     -   5. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═OSO₃H;     -   6. A compound wherein Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═SO₃H;     -   7. A compound wherein Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═OSO₃1H;     -   8. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H;     -   9. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H;     -   10. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H,         R₄═SO₃H;     -   11. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H,         R₄═OSO₃H;     -   12. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H;     -   13. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H;     -   14. A compound wherein Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H;     -   15. A compound wherein Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H;     -   16. A compound wherein Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H     -   17. A compound wherein Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H;     -   18. A compound wherein Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═SO₃H;     -   19. A compound wherein Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H;     -   20. A compound wherein Z═OH, R₂═NHSO₃H, R₁, R₃ to R₈═H;     -   21. A compound wherein Z═OH, R₂ to R₈═H, R₁═CH₂SO₃H;     -   22. A compound wherein Z═OH, R₂ to R₈═H, R₁═CH₂OSO₃H;     -   23. A compound wherein Z═OH, R₂ to R₈═H, R₁═SO₃H;     -   24. A compound wherein Z═OH, R₂ to R₈═H, R₁═OSO₃H;     -   25. A compound wherein Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═SO₃H;     -   26. A compound wherein Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H;     -   27. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H;     -   28. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H;     -   29. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H,         R₄═SO₃H;     -   30. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H,         R₄═OSO₃H;     -   31. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H;     -   32. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H;     -   33. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═SO₃H;     -   34. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═OSO₃H;     -   35. A compound wherein Z═OH, R₂═NH₂, R═R₈═H, R₃ to R₆═H,         R₇═SO₃H;     -   36. A compound wherein Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H,         R₇═OSO₃H;     -   37. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H;     -   38. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H;     -   39. A compound wherein Z═NH₂, R₁═NHSO₃H, R₂ to R₈═H;     -   40. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂SO₃H;     -   41. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂OSO₃H;     -   42. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═SO₃H;     -   43. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═OSO₃H;     -   44. A compound wherein Z═R₁═NH₂, R₃ to R₈═H, R₂═SO₃H;     -   45. A compound wherein Z═R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H;     -   46. A compound wherein Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H;     -   47. A compound wherein Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H;     -   48. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H;     -   49. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H;     -   50. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═SO₃H;     -   51. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H;     -   52. A compound wherein Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H;     -   53. A compound wherein Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H;     -   54. A compound wherein Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H;     -   55. A compound wherein Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H;     -   56. A compound wherein Z═R₁═NH₂, R₂ to R₇═H, R₈═SO₃H;     -   57. A compound wherein Z═R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H;     -   58. A compound wherein Z═NH₂, R₂═NHSO₃H, R₁ and R₃ to R₈═H;     -   59. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═CH₂SO₃H;     -   60. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═CH₂OSO₃H;     -   61. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═SO₃H;     -   62. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═OSO₃H;     -   63. A compound wherein Z═R₂═NH₂, R₃ to R₈═H, R₁═SO₃H;     -   64. A compound wherein Z═R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H;     -   65. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H;     -   66. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H;     -   67. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H;     -   68. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H;     -   69. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H, R₅═SO     -   70. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,         R₅═OSO₃H;     -   71. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═SO₃H;     -   72. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,         R₆═OSO₃H;     -   73. A compound wherein Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═SO₃H;     -   74. A compound wherein Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H;     -   75. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H;     -   76. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H.         h) In the compound of the present invention of the formula (Ia)         wherein the compound is selected from the group consisting of         aspartic acid, asparagine and corresponding de-amino analogs:     -   1. L-Aspartic acid, N-Sulfonic acid     -   2. L-Aspartic acid, 2β-sulfonic acid     -   3. L-Aspartic acid, 2β-sulfate     -   4. L-aspartic acid, 3α-sulfonic acid     -   5. L-aspartic acid, 3α-sulfate     -   6. L-aspartic acid, 3β-sulfonic acid     -   7. L-aspartic acid, 3β-sulfate     -   8. 2α,3-dicarboxy, propane-1-sulfonic acid     -   9. 2α,3-dicarboxy, propane-1-sulfate     -   10. 1α,2-carboxy ethane sulfonic acid     -   11. 1α,2-carboxy ethane sulfate     -   12. D-aspartic acid, N-sulfonic acid     -   13. 2β,3-carboxy, propane-1-sulfonic acid     -   14. 2β,3-carboxy, propane-1-sulfate     -   15. 1β,2-carboxy ethane-1-sulfonic acid     -   16. 1β,2-carboxy ethane-1-sulfate     -   17. D-aspartic acid, 2α-sulfonic acid     -   18. D-aspartic acid, 2α-sulfonic acid     -   19. D-Aspartic acid, 3α-sulfonic acid     -   20. D-Aspartic acid, 3α-sulfate     -   21. D-Aspartic acid, 3β-sulfonic acid     -   22. D-aspartic acid, 3β-sulfate     -   23. L-asparagine, N-sulfonic acid     -   24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   25. 2α-carboxy, 3-carboxamido, propane-1-sulfate     -   26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid     -   27. 1α-carboxy, 2-carboxamido, ethane sulfate     -   28. L-asparagine, 2β-sulfonic acid     -   29. -asparagine, 2β-sulfate     -   30. L-asparagine, 3α-sulfonic acid     -   31. L-asparagine, 3α-sulfate     -   32. L-asparagine, 3β-sulfonic acid     -   33. L-asparagine, 3β-sulfate     -   34. D-asparagine, N-sulfonic acid     -   35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   36. 2β-carboxy, 3-carboxamido, propane-1-sulfate     -   37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid     -   38. 1β-carboxy, 2-carboxamido, ethane sulfate     -   39. D-asparagine, 2α-sulfonic acid     -   40. D-asparagine, 2α-sulfate     -   41. D-asparagine, 3α-sulfonic acid     -   42. D-asparagine, 3α-sulfate     -   43. D-asparagine, 3β-sulfonic acid     -   44. D-asparagine, 3β-sulfate.         i) In the compound of the present invention of the formula (Ib)         wherein the compound is selected from the group consisting of         glutamic acid, glutamine and corresponding de-amino analogs:     -   1. 1 L-glutamic acid, N-sulfonic acid     -   2. 2α,4-dicarboxy, butane-1-sulfonic acid     -   3. 2α,4-dicarboxy, butane-1-sulfate     -   4. 1α,3-dicarboxy, propane sulfonic acid     -   5. 1α,3-dicarboxy, propane sulfate     -   6. 1β,3-dicarboxy, propane sulfate     -   7. 1β,3-dicarboxy, propane sulfonic acid     -   8. L-glutamic acid, 2β-sulfonic acid     -   9. L-glutamic acid, 2β-sulfate     -   10. L-glutamic acid, 3α-sulfonic acid     -   11. L-glutamic acid, 3α-sulfate     -   12. L-glutamic acid, 3β-sulfonic acid     -   13. L-glutamic acid, 3β-sulfate     -   14. L-glutamic acid, 4α-sulfonic acid     -   15. L-glutamic acid, 4α-sulfate     -   16. L-glutamic acid, 4β-sulfonic acid     -   17. L-glutamic acid, 4β-sulfate     -   18. D-glutamic acid, N-sulfonic acid     -   19. 2β,4-dicarboxy, butane-1-sulfonic acid     -   20. 2β,4-dicarboxy, butane-1-sulfate     -   21. D-glutamic acid, 2α-sulfonic acid     -   22. D-glutamic acid, 2α-sulfate     -   23. D-glutamic acid, 3α-sulfonic acid     -   24. D-glutamic acid, 3α-sulfate     -   25. D-glutamic acid, 3β-sulfonic acid     -   26. D-glutamic acid, 3β-sulfate     -   27. D-glutamic acid, 4α-sulfonic acid     -   28. D-glutamic acid, 4α-sulfate     -   29. D-glutamic acid, 4β-sulfonic acid     -   30. D-glutamic acid, 4β-sulfate     -   31. L-glutamine, N-sulfonic acid     -   32. L-glutamine, 2β-sulfonic acid     -   33. L-glutamine, 2β-sulfate     -   34. L-glutamine, 3α-sulfonic acid     -   35. L-glutamine, 3α-sulfate     -   36. L-glutamine, 3β-sulfonic acid     -   37. L-glutamine, 3β-sulfate     -   38. L-glutamine, 4α-sulfonic acid     -   39. L-glutamine, 4α-sulfate     -   40. L-glutamine, 4β-sulfonic acid     -   41. L-glutamine, 4β-sulfate     -   42. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid     -   43. 2α-carboxy, 4-carboxamido, butane-1-sulfate     -   44. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   45. 1α-carboxy, 3-carboxamido, propane-1-sulfate     -   46. 1β-carboxy, 3-carboxamido, propane-1-sulfate     -   47. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid     -   48. D-glutamine, N-sulfonic acid     -   49. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid     -   50. 2β-carboxy, 4-carboxamido, butane-1-sulfate     -   51. D-glutamine, 2α-sulfonic acid     -   52. D-glutamine, 2α-sulfate     -   53. D-glutamine, 3α-sulfonic acid     -   54. D-glutamine, 3α-sulfate     -   55. D-glutamine, 3β-sulfonic acid     -   56. D-glutamine, 3β-sulfate     -   57. D-glutamine, 4α-sulfonic acid     -   58. D-glutamine, 4α-sulfate     -   59. D-glutamine, 4β-sulfonic acid     -   60. D-glutamine, 4β-sulfate         j) In the compound of the present invention of the formula (Ic)         wherein the compound is selected from the group consisting of         homoglutamic acid, homoglutamine and corresponding de-amino         analogs:     -   1. L-homoglutamic acid, N-sulfonic acid     -   2. Pentane-2α,5-dicarboxy-1-sulfonic acid     -   3. Pentane-2α,5-dicarboxy-1-sulfate     -   4. Butane-1α,4-dicarboxy-1-sulfonic acid     -   5. Butane-1α,4-dicarboxy-1-sulfate     -   6. L-homoglutamic acid, 2β-sulfonic acid     -   7. L-homoglutamic acid, 2β-sulfate     -   8. L-homoglutamic acid, 3α-sulfonic acid     -   9. L-homoglutamic acid, 3α-sulfate     -   10. L-homoglutamic acid, 3β-sulfonic acid     -   11. L-homoglutamic acid, 3β-sulfate     -   12. L-homoglutamic acid, 4α-sulfonic acid     -   13. L-homoglutamic acid, 4α-sulfate     -   14. L-homoglutamic acid, 4β-sulfonic acid     -   15. L-homoglutamic acid, 4β-sulfate     -   16. L-homoglutamic acid, 5α-sulfonic acid     -   17. L-homoglutamic acid, 5α-sulfate     -   18. L-homoglutamic acid, 5β-sulfonic acid     -   19. L-homoglutamic acid, 5β-sulfate     -   20. D-homoglutamic acid, N-sulfonic acid     -   21. Pentane-2β,5-dicarboxy-1-sulfonic acid     -   22. Pentane-2β,5-dicarboxy-1-sulfate     -   23. Butane-1β,4-dicarboxy-1-sulfonic acid     -   24. Butane-1β,4-dicarboxy-1-sulfate     -   25. D-homoglutamic acid, 2α-sulfonic acid     -   26. D-homoglutamic acid, 2α-sulfate     -   27. D-homoglutamic acid, 3α-sulfonic acid     -   28. D-homoglutamic acid, 3α-sulfate     -   29. D-homoglutamic acid, 3β-sulfonic acid     -   30. D-homoglutamic acid, 3β-sulfate     -   31. D-homoglutamic acid, 4α-sulfonic acid     -   32. D-homoglutamic acid, 4α-sulfate     -   33. D-homoglutamic acid, 4β-sulfonic acid     -   34. D-homoglutamic acid, 4β-sulfate     -   35. D-homoglutamic acid, 5α-sulfonic acid     -   36. D-homoglutamic acid, 5α-sulfate     -   37. D-homoglutamic acid, 5β-sulfonic acid     -   38. D-homoglutamic acid, 5β-sulfate     -   39. L-homoglutamine, N-sulfonic acid     -   40. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid     -   41. Pentane-2α-carboxy, 5-carboxamido-1-sulfate     -   42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid     -   43. Butane-1α-carboxy, 4-carboxamido-1-sulfate     -   44. L-homoglutamine, 2β-sulfonic acid     -   45. L-homoglutamine, 2β-sulfate     -   46. L-homoglutamine, 3α-sulfonic acid     -   47. L-homoglutamine, 3α-sulfate     -   48. L-homoglutamine, 3β-sulfonic acid     -   49. L-homoglutamine, 3β-sulfate     -   50. L-homoglutamine, 4α-sulfonic acid     -   51. L-homoglutamine, 4α-sulfate     -   52. L-homoglutamine, 4β-sulfonic acid     -   53. L-homoglutamine, 4β-sulfate     -   54. L-homoglutamine, 5α-sulfonic acid     -   55. L-homoglutamine, 5α-sulfate     -   56. L-homoglutamine, 5β-sulfonic acid     -   57. L-homoglutamine, 5β-sulfate     -   58. D-homoglutamine, N-sulfonic acid     -   59. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid     -   60. Pentane-2β-carboxy, 5-carboxamido-1-sulfate     -   61. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid     -   62. Butane-1β-carboxy, 4-carboxamido-1-sulfate     -   63. D-homoglutamine, 2α-sulfonic acid     -   64. D-homoglutamine, 2α-sulfate     -   65. D-homoglutamine, 3α-sulfonic acid     -   66. D-homoglutamine, 3α-sulfate     -   67. D-homoglutamine, 3β-sulfonic acid     -   68. D-homoglutamine, 3β-sulfate     -   69. D-homoglutamine, 4α-sulfonic acid     -   70. D-homoglutamine, 4α-sulfate     -   71. D-homoglutamine, 4β-sulfonic acid     -   72. D-homoglutamine, 4β-sulfate     -   73. D-homoglutamine, 5α-sulfonic acid     -   74. D-homoglutamine, 5α-sulfate     -   75. D-homoglutamine, 5β-sulfonic acid     -   76. D-homoglutamine, 5β-sulfate

The preferable specific compounds of the formulae (Ia), (Ib) and (Ic) are the derivatives of aspartic acid, asparagine and corresponding de-amino analogs (Table 1), glutamic acid, glutamine and corresponding de-amino analogs (Table 2) and homoglutamic acid, homoglutamine and corresponding de-amino analogs (Table 3) and non toxic salts thereof and example compounds. TABLE 1

1. L-Aspartic acid, N-Sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ = R₃ = R₄ = H 2. L-Aspartic acid, 2β-sulfonic acid Z = OH, R₁ = NH₂, R₃ = R₄ = H, R₂ = SO₃H 3. L-Aspartic acid, 2β-sulfate Z = OH, R₁ = NH₂, R₃ = R₄ = H, R₂ = OSO₃H 4. L-aspartic acid, 3α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₄ = H, R₃ = SO₃H 5. L-aspartic acid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = R₄ = H, R₃ = OSO₃H 6. L-aspartic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = H, R₄ = SO₃H 7. L-aspartic acid, 3β-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ = H, R₄ = OSO₃H 8. 2α, 3-dicarboxy, propane-1-sulfonic acid Z = OH, R₁ = R₃ = R₄ = H, R₂ = CH₂SO₃H 9. 2α, 3-dicarboxy, propane-1-sulfate Z = OH, R₁ = R₃ = R₄ = H, R₂ = CH₂OSO₃H 10. 1α, 2-carboxy ethane sulfonic acid Z = OH, R₁ = R₃ = R₄ = H, R₂ = SO₃H 11. 1α, 2-carboxy ethane sulfate Z = OH, R₁ = R₃ = R₄ = H, R₂ = OSO₃H 12. D-aspartic acid, N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁ = R₃= R₄ = H 13. 2β, 3-carboxy, propane-1-sulfonic acid Z = OH, R₂ = H, R₁ = CH₂SO₃H 14. 2β, 3-carboxy, propane-1-sulfate Z = OH, R₂ = H, R₁ = CH₂OSO₃H 15. 1β, 2-carboxy ethane-1-sulfonic acid Z = OH, R₂ = H, R₁ = SO₃H 16. 1β, 2-carboxy ethane-1-sulfate Z = OH, R₂ = H, R₁ = OSO₃H 17. D-aspartic acid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 18. D-aspartic acid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 19. D-Aspartic acid, 3α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₄ = H, R₃ = SO₃H 20. D-Aspartic acid, 3α-sulfate Z = OH, R₂ = NH₂, R₁ = R₄ = H, R₃ = OSO₃H 21. D-Aspartic acid, 3β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = H, R₄ = SO₃H 22. D-aspartic acid, 3β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = H, R₄ = OSO₃H 23. L-asparagine, N-sulfonic acid Z = NH₂, R₁ = NHSO₃H, R₂ = R₃ = R₄ = H 24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₁ = H, R₂ = CH₂SO₃H 25. 2α-carboxy, 3-carboxamido, propane-1-sulfate Z = NH₂, R₁ = H, R₂ = CH₂OSO₃H 26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid Z = NH₂, R₁ = H, R₂ = SO₃H 27. 1α-carboxy, 2-carboxamido, ethane sulfate Z = NH₂, R₁ = H, R₂ = OSO₃H 28. L-asparagine, 2β-sulfonic acid Z = R₁ = NH₂, R₂ = R₄ = H, R₂ = SO₃H 29. L-asparagine, 2β-sulfate Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = OSO₃H 30. L-asparagine, 3α-sulfonic acid Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = SO₃H 31. L-asparagine, 3α-sulfate Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = OSO₃H 32. L-asparagine, 3β-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = H, R₄ = SO₃H 33. L-asparagine, 3β-sulfate Z = R₁ = NH₂, R₂ = R₃ = H, R₄ = OSO₃H 34. D-asparagine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H, R₁ = R₃ = R₄ = H 35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₂ to R₄ = H, R₁ = CH₂SO₃H 36. 2β-carboxy, 3-carboxamido, propane-1-sulfate Z = NH₂, R₂ to R₄ = H, R₁ = CH₂SO₃H 37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid] Z = OH, R₂ to R₄ = H, R₁ = SO₃H 38. 1β-carboxy, 2-carboxamido, ethane sulfate Z = OH, R₂ to R₄ = H, R₁ = OSO₃H 39. D-asparagine, 2α-sulfonic acid Z = R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 40. D-asparagine, 2α-sulfate Z = R₂ = NH₂, R₃ = R₄ = H, R₁ = OSO₃H 41. D-asparagine, 3α-sulfonic acid Z = R₂ = NH₂, R₁ = R₄ = H, R₃ = SO₃H 42. D-asparagine, 3α-sulfate Z = R₂ = NH₂, R₁ = R₄ = H, R₃ = OSO₃H 43. D-asparagine, 3β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = H, R₄ = SO₃H 44. D-asparagine, 3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = H, R₄ = OSO₃H

TABLE 2

1. L-glutamic acid, N-sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ = R₃ = R₄ = R₅ = R₆ = H 2. 2α, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₁, R₃ to R₆ = H, R₂ = CH₂SO₃H 3. 2α, 4-dicarboxy, butane-1-sulfate Z = OH, R₁, R₃ to R₆ = H, R₂ = CH₂OSO₃H 4. 1α, 3-dicarboxy, propane sulfonic acid Z = OH, R₁, R₃ to R₆ = H, R₂ = SO₃H 5. 1α, 3-dicarboxy, propane sulfate Z = OH, R₁, R₃ to R₆ = H, R₂ = OSO₃H 6. 1β, 3-dicarboxy, propane sulfate Z = OH, R₂ to R₆ = H, R₁ = OSO₃H 7. 1β, 3-dicarboxy, propane sulfonic acid Z = OH, R₂ to R₆ = H, R₁ = SO₃H 8. L-glutamic acid, 2β-sulfonic acid Z = OH, R₁ = NH₂, R₃ to R₆ = H, R₂ = SO₃H 9. L-glutamic acid, 2β-sulfate Z = OH, R₁ = NH₂, R₃ to R₆ = H, R₂ = OSO₃H 10. L-glutamic acid, 3α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₆ = H, R₃ = SO₃H 11. L-glutamic acid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₆ = H, R₃ = OSO₃H 12. L-glutamic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = R₅ = R₆ = H, R₄ = SO₃H 13. L-glutamic acid, 3β-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ = R₅ = R₆ = H, R₄ = OSO₃H 14. L-glutamic acid, 4α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = SO₃H 15. L-glutamic acid, 4α-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = OSO₃H 16. L-glutamic acid, 4β-sulfonic acid Z = OH, R₁ = NH₂, R₂ to R₅ = H, R₆ = SO₃H 17. L-glutamic acid, 4β-sulfate Z = OH, R₁ = NH₂, R₂ to R₅ = H, R₆ = OSO₃H 18. D-glutamic acid, N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁, R₃ to R₆ = H 19. 2β, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₂ to R₆ = H, R₁ = CH₂SO₃H 20. 2β, 4-dicarboxy, butane-1-sulfate Z = OH, R₂ to R₆ = H, R₁ = CH₂OSO₃H 21. D-glutamic acid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ to R₆ H, R₁ = SO₃H 22. D-glutamic acid, 2α-sulfate Z = OH, R₂ = NH₂, R₃ to R₆ H, R₁ = OSO₃H 23. D-glutamic acid, 3α-sulfonic acid Z = OH, R₂ = NH₂, R₁, R₄ to R₆ H, R₃ = SO₃H 24. D-glutamic acid, 3α-sulfate Z = OH, R₂ = NH₂, R₁, R₄ to R₆ H, R₃ = OSO₃H 25. D-glutamic acid, 3β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = SO₃H 26. D-glutamic acid, 3β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = OSO₃H 27. D-glutamic acid, 4α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₆ = H, R₅ = SO₃H 28. D-glutamic acid, 4α-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₆ = H, R₅ = OSO₃H 29. D-glutamic acid, 4β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = SO₃H 30. D-glutamic acid, 4β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = OSO₃H 31. L-glutamine, N-sulfonic acid Z = NH₂, R₁ = NHSO₃H, R₂ to R₆ = H 32. L-glutamine, 2β-sulfonic acid Z = R₁ = NH₂, R₃ to R₆ = H, R₂ = SO₃H 33. L-glutamine, 2β-sulfate Z = R₁ = NH₂, R₃ to R₆= H, R₂ = OSO₃H 34. L-glutamine, 3α-sulfonic acid Z = R₁ = NH₂, R₂ = H, R₃ to R₆ = H, R₃ = SO₃H 35. L-glutamine, 3α-sulfate Z = R₁ = NH₂, R₂ = H, R₃ to R₆ = H, R₃ = OSO₃H 36. L-glutamine, 3β-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = R₅ = R₆ = H, R₄ = SO₃H 37. L-glutamine, 3β-sulfate Z = R₁ = NH₂, R₂ = R₃ = R₅ = R₆ = H, R₄ = OSO₃H 38. L-glutamine, 4α-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = SO₃H 39. L-glutamine, 4α-sulfate Z = R₁ = NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = OSO₃H 40. L-glutamine, 4β-sulfonic acid Z = R₁ = NH₂, R₂ to R₅ = H, R₆ = SO₃H 41. L-glutamine, 4β-sulfate Z = R₁ = NH₂, R₂ to R₅ = H, R₆ = OSO₃H 42. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid Z = NH₂, R₁, R₃ to R₆ = H, R₂ = CH₂SO₃H 43. 2α-carboxy, 4-carboxamido, butane-1-sulfate Z = NH₂, R₁, R₃ to R₆ = H, R₂ = CH₂OSO₃H 44. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₁, R₃ to R₆ = H, R₂ = SO₃H 45. 1α-carboxy, 3-carboxamido, propane-1-sulfate Z = NH₂, R₁, R₃ to R₆ = H, R₂ = OSO₃H 46. 1β-carboxy, 3-carboxamido, propane-1-sulfate Z = NH₂, R₂ to R₆ = H, R₁ = OSO₃H 47. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₂ to R₆ = H, R₁ = SO₃H 48. D-glutamine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H; R₁ = H, R₃ to R₆ = H 49. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid Z = NH₂, R₂ to R₆ = H, R₁ = CH₂SO₃H 50. 2β-carboxy, 4-carboxamido, butane-1-sulfate Z = NH₂, R₂ to R₆ = H, R₁ = CH₂OSO₃H 51. D-glutamine, 2α-sulfonic acid Z = NH₂, R₂ = NH₂, R₃ to R₆ = H, R₁ = SO₃H 52. D-glutamine, 2α-sulfate Z = NH₂, R₂ = NH₂, R₃ to R₆ = H, R₁ = OSO₃H 53. D-glutamine, 3α-sulfonic acid Z = NH₂, R₂ = NH₂, R₁, R₄ to R₆ H, R₃ = SO₃H 54. D-glutamine, 3α-sulfate Z = R₂ = NH₂, R₁, R₄ to R₆ H, R₃ = OSO₃H 55. D-glutamine, 3β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = SO₃H 56. D-glutamine, 3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = OSO₃H 57. D-glutamine, 4α-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₄ = R₆ = H, R₅ = SO₃H 58. D-glutamine, 4α-sulfate Z = R₂ = NH₂, R₁ = R₃ = R₄ = R₆ = H, R₅ = OSO₃H 59. D-glutamine, 4β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = SO₃H 60. D-glutamine, 4β-sulfate Z = R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = OSO₃H

TABLE 3

1. L-homoglutamic acid, N-sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ to R₈ = H 2. Pentane-2α, 5-dicarboxy-1-sulfonic acid Z = OH, R₁, R₃ to R₈ = H, R₂ = CH₂SO₃H 3. Pentane-2α, 5-dicarboxy-1-sulfate Z = OH, R₁, R₃ to R₈ = H, R₂ = CH₂OSO₃H 4. Butane-1α, 4-dicarboxy-1-sulfonic acid Z = OH, R₁, R₃ to R₈ = H, R₂ = SO₃H 5. Butane-1α, 4-dicarboxy-1-sulfate Z = OH, R₁, R₃ to R₈ = H, R₂ = OSO₃H 6. L-homoglutamic acid, 2β-sulfonic acid Z = OH, R₁ = NH₂, R₃ to R₈ = H, R₂ = SO₃H 7. L-homoglutamic acid, 2β-sulfate Z = OH, R₁ = NH₂, R₃ to R₈ = H, R₂ = OSO₃H 8. L-homoglutamic acid, 3α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₈ H, R₃ = SO₃H 9. L-homoglutamic acid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₈ H, R₃ = OSO₃H 10. L-homoglutamic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 11. L-homoglutamic acid, 3β-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 12. L-homoglutamic acid, 4α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = SO₃H 13. L-homoglutamic acid, 4α-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 14. L-homoglutamic acid, 4β-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 15. L-homoglutamic acid, 4β-sulfate Z = OH, R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = OSO₃H 16. L-homoglutamic acid, 5α-sulfonic acid Z = OH, R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = SO₃H 17. L-homoglutamic acid, 5α-sulfate Z = OH, R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = OSO₃H 18. L-homoglutamic acid, 5β-sulfonic acid Z = OH, R₁ = NH₂, R₂ to R₇ = H, R₈ = SO₃H 19. L-homoglutamic acid, 5β-sulfate Z = OH, R₁ = NH₂, R₂ to R₇ = H, R₈ = OSO₃H 20. D-homoglutamic acid, N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁, R₃ to R₈ = H 21. Pentane-2β, 5-dicarboxy-1-sulfonic acid Z = OH, R₂ to R₈ = H, R₁ = CH₂SO₃H 22. Pentane-2β, 5-dicarboxy-1-sulfate Z= OH, R₂ to R₈ = H, R₁ = CH₂OSO₃H 23. Butane-1β, 4-dicarboxy-1-sulfonic acid Z = OH, R₂ to R₈ = H, R₁ = SO₃H 24. Butane-1β, 4-dicarboxy-1-sulfate Z = OH, R₂ to R₈ = H, R₁ = OSO₃H 25. D-homoglutamic acid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ to R₈ = H, R₁ = SO₃H 26. D-homoglutamic acid, 2α-sulfate Z = OH, R₂ = NH₂, R₃ to R₈ = H, R₁ = OSO₃H 27. D-homoglutamic acid, 3α-sulfonic acid Z = OH, R₂ = NH₂, R₁, R₄ to R₈ H, R₃ = SO₃H 28. D-homoglutamic acid, 3α-sulfate Z = OH, R₂ = NH₂, R₁, R₄ to R₈ H, R₃ = OSO₃H 29. D-homoglutamic acid, 3β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 30. D-homoglutamic acid, 3β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 31. D-homoglutamic acid, 4α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = SO₃H 32. D-homoglutamic acid, 4α-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 33. D-homoglutamic acid, 4β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 34. D-homoglutamic acid, 4β-sulfate Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = OSO₃H 35. D-homoglutamic acid, 5α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = SO₃H 36. D-homoglutamic acid, 5α-sulfate Z = OH, R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = OSO₃H 37. D-homoglutamic acid, 5β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ = SO₃H 38. D-homoglutamic acid, 5β-sulfate Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ = OSO₃H 39. L-homoglutamine, N-sulfonic acid Z = NH₂, R₁ = NHSO₃H, R₂ to R₈ = H 40. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = CH₂SO₃H 41. Pentane-2α-carboxy, 5-carboxamido-1-sulfate Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = CH₂OSO₃H 42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = SO₃H 43. Butane-1α-carboxy, 4-carboxamido-1-sulfate Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = OSO₃H 44. L-homoglutamine, 2β-sulfonic acid Z = R₁ = NH₂, R₃ to R₈ = H, R₂ = SO₃H 45. L-homoglutamine, 2β-sulfate Z = R₁ = NH₂, R₃ to R₈ = H, R₂ = OSO₃H 46. L-homoglutamine, 3α-sulfonic acid Z = R₁ = NH₂, R₂ = H, R₄ to R₈ = H, R₃ = SO₃H 47. L-homoglutamine, 3α-sulfate Z = R₁ = NH₂, R₂ = H, R₄ to R₈ = H, R₃ = OSO₃H 48. L-homoglutamine, 3β-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 49. L-homoglutamine, 3β-sulfate Z = R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 50. L-homoglutamine, 4α-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = SO₃H 51. L-homoglutamine, 4α-sulfate Z = R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 52. L-homoglutamine, 4β-sulfonic acid Z = R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 53. L-homoglutamine, 4β-sulfate Z = R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = OSO₃H 54. L-homoglutamine, 5α-sulfonic acid Z = R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = SO₃H 55. L-homoglutamine, 5α-sulfate Z = R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = OSO₃H 56. L-homoglutamine, 5β-sulfonic acid Z = R₁ = NH₂, R₂ to R₇ = H, R₈ = SO₃H 57. L-homoglutamine, 5β-sulfate Z = R₁ = NH₂, R₂ to R₇ = H, R₈ = OSO₃H 58. D-homoglutamine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H, R₁ and R₃ to R₈ = H 59. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid Z = NH₂, R₂ to R₈ = H, R₁ = CH₂SO₃H 60. Pentane-2β-carboxy, 5-carboxamido-1-sulfate Z = NH₂, R₂ to R₈ = H, R₁ = CH₂OSO₃H 61. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid Z = NH₂, R₂ to R₈ = H, R₁ = SO₃H 62. Butane-1β-carboxy, 4-carboxamido-1-sulfate Z = NH₂, R₂ to R₈ = H, R₁ = OSO₃H 63. D-homoglutamine, 2α-sulfonic acid Z = R₂ = NH₂, R₃ to R₈ H, R₁ = SO₃H 64. D-homoglutamine, 2α-sulfate Z = R₂ = NH₂, R₃ to R₈ H, R₁ = OSO₃H 65. D-homoglutamine, 3α-sulfonic acid Z = R₂ = NH₂, R₁, R₄ to R₈ H, R₃ = SO₃H 66. D-homoglutamine, 3α-sulfate Z = R₂ = NH₂, R₁, R₄ to R₈ H, R₃ = OSO₃H 67. D-homoglutamine, 3β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 68. D-homoglutamine, 3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 69. D-homoglutamine, 4α-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = SO₃H 70. D-homoglutamine, 4α-sulfate Z = R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 71. D-homoglutamine, 4β-sulfonic acid Z = R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 72. D-homoglutamine, 4β-sulfate Z = R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = OSO₃H 73. D-homoglutamine, 5α-sulfonic acid Z = R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = SO₃H 74. D-homoglutamine, 5α-sulfate Z = R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = OSO₃H 75. D-homoglutamine, 5β-sulfonic acid Z = R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ = SO₃H 76. D-homoglutamine, 5β-sulfate Z = R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ = OSO₃H

REFERENCE EXAMPLE

The following reference example and examples illustrate the present invention but do not limit the present invention.

The solvents in the parenthesis show the developing and eluting solvents and the ratios of the solvent used are by volume in the chromatographic separation or TLC.

The solvents in the parenthesis in NMR show the solvents used in measurement.

REFERENCE EXAMPLE AND EXAMPLE

The following reference example and examples illustrate the present invention but do not limit the present invention. The solvents in the parenthesis show the developing and eluting solvents and the ratios of the solvent used are by volume in the chromatographic separation or TLC. The solvents in the parenthesis in NMR show the solvents used in measurement.

Reference Example 1

L-Glutamyl, N-Sulfonic Acid from Glutamic Acid Mono Tertiary Butyl Ester

Glutamic acid monotertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the product L-glutamyl, N-sulfonic acid (calculated for C5H8NO7S; 226.0026).

Reference Example 2

L-Glutamyl, N-Sulfonic Acid from Glutamic Acid Di Tertiary Butyl Ester

Glutamic acid ditertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the product L-glutamyl, N-sulfonic acid (calculated for C₅H₈NO7S; 226.0026).

Reference Example 3

L-Aspartyl, N-Sulfonic Acid from L-Aspartic Acid Di Tertiary Butyl Ester

L-aspartic acid di tertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3 eq.). Result solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 211.9885 confirmed the structure of the product L-aspartyl, N-sulfonic acid (calculated for C4H6NO7S; 211.9870).

Reference Example 4

L-Homoglutamyl, N-Sulfonic Acid from L-Homoglutamic Acid Di Tertiary Butyl Ester

L-Homoglutamic acid di tertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 240.0169 confirmed the structure of the product L-Homoglutamyl, N-sulfonic acid (calculated for C6H10NO7S; 240.0182).

Reference Example 5

The calcium salt of L-glutamyl-N-sulphonic acid was prepared by adding 1 M equivalent of CaCl₂ solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table A). TABLE A Effect of compound 1 (L-glutamyl-N-sulphonic acid, Ca salt) on osteoclast formation Number of TRAP-positive multinuclear cells/well Culture of 96 well plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 138.00 ± 9.37  — M-CSF + RANKL + 109.67 ± 9.79  21.01 compound 1 (0.5 μg/ml) M-CSF + RANKL + 52.17 ± 6.42  62.19 compound 1 (1.5 μg/ml) M-CSF + RANKL + 14.67 ± 1.98  89.36 compound 1 (3.0 μg/ml) M-CSF + RANKL + 2.83 ± 1.05 97.94 compound 1 (5.0 μg/ml) Culture of murine bone marrow cells in the presence of M-CSF and RANKL induces the formation of osteoclasts, which were detected as TRAP-positive cells. A dose dependent inhibition in the number of osteoclast cells generated as observed with increasing dose of compound 1. Values given are the mean±SD of five separate experiments

Reference Example 6

The calcium salt of L-glutamic acid was prepared by adding 1 M equivalent of CaCl₂ solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table B). TABLE B Effect of L-glutamic acid, calcium salt on osteoclast formation Number of TRAP-positive multinuclear cells/well of 96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 158.33 ± 12.00 — M-CSF + RANKL + 167.17 ± 7.95  0 compound 2 (0.5 μg/ml) M-CSF + RANKL + 152.83 ± 10.47 3.47 compound 2 (1.5 μg/ml) M-CSF + RANKL + 130.50 ± 13.57 17.37 compound 2 (3.0 μg/ml) M-CSF + RANKL + 119.50 ± 10.00 24.52 compound 2 (5.0 μg/ml) For detail see legend to example 5

Reference Example 7

The L-glutamyl-N-sulphonic acid prepared as described in Examples 1 & 2 was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table D). TABLE-D Effect of L-glutamyl-N-sulphonic acid on osteoclast formation Number of TRAP-positive multinuclear cells/well of 96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL  146.83 ± 11.89 — M-CSF + RANKL + 154.67 ± 8.43 0 compound 3 (0.5 μg/ml) M-CSF + RANKL + 150.33 ± 8.82 0 compound 3 (1.5 μg/ml) M-CSF + RANKL + 112.67 ± 8.63 23.23 compound 3 (3.0 μg/ml) M-CSF + RANKL + 110.00 ± 6.72 25.08 compound 3 (5.0 μg/ml) For detail see legend to example 5

Reference Example 8

The L-glutamic acid was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table E). TABLE E Effect of L-glutamic acid on osteoclast formation Number of TRAP-positive multinuclear cells/well of 96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 156.00 ± 12.26 0 M-CSF + RANKL + 173.33 ± 6.50  0 compound 4 (0.5 μg/ml) M-CSF + RANKL + 155.00 ± 8.23  0.64 compound 4 (1.5 μg/ml) M-CSF + RANKL + 145.83 ± 14.71 7.05 compound 4 (3.0 μg/ml) M-CSF + RANKL + 112.67 ± 10.74 27.77 compound 4 (5.0 μg/ml) For detail see legend to example 5

Reference Example 9

The L-Aspartic acid, N-sulphonic acid as prepared in example 3 was mixed with 1 M equivalent of CaCl₂ solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table F). TABLE F Effect of L-Aspartic acid, N-sulphonic acid calcium salt on osteoclast formation Number of TRAP-positive multinuclear cells/well of 96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 158.33 ± 11.26 0 M-CSF + RANKL + 127.30 ± 5.50  19.70 compound 4 (0.5 μg/ml) M-CSF + RANKL + 86.23 ± 7.23 45.16 compound 4 (1.5 μg/ml) M-CSF + RANKL + 44.50 ± 4.80 71.90 compound 4 (3.0 μg/ml) M-CSF + RANKL + 26.67 ± 0.73 83.26 compound 4 (5.0 μg/ml) For detail see legend to example 5 Reference Example 10

L-homoglutamic acid, N-sulphonic acid as prepared in example 4 was mixed with 1 M equivalent of CaCl₂ solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table G). TABLE G Effect of L-homoglutamic acid, N-sulphonic acid, calcium salt on osteoclast formation Number of TRAP-positive multinuclear cells/well of 96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 146..83 ± 12.00  — M-CSF + RANKL + 138.57 ± 7.95  5.55 compound 2 (0.5 μg/ml) M-CSF + RANKL + 106.23 ± 10.47 27.60 compound 2 (1.5 μg/ml) M-CSF + RANKL +  78.57 ± 13.57 46.40 compound 2 (3.0 μg/ml) M-CSF + RANKL +  46.22 ± 10.00 68.50 compound 2 (5.0 μg/ml) For detail see legend to example 5

Reference Example 11

A. In Vitro Osteoclastogenesis Assay

For in vitro osteoclastogenesis bone marrow cells were isolated from 5-to 8-wk-old Balb/c mice. Mice were sacrificed by cervical dislocation and femora and tibiae were aseptically removed and dissected free of adherent soft tissues. The bone ends were cut, and the marrow cavity was flushed out with medium MEM from one end of the bone using a sterile 21-gauge needle. The bone marrow suspension was carefully agitated with a plastic Pasteur pipette to obtain a single-cell suspension. The cells were washed twice and resuspended (10⁶ cells/ml) in {overscore (α)}MEM containing 10% FBS. Stromal cell-free, M-CSF-dependent, osteoclast precursor cells were prepared from these cells as previously described (Wani et al. 1999). Briefly, bone marrow cells were incubated for 24 h in {overscore (α)}MEM containing 10% FBS in the presence of M-CSF (10 ng/ml) at a density of 3×10⁵ cells/ml in a 75 cm² flask. After 24 h, nonadherent cells were harvested and layered on a Ficoll-Hypaque gradient. Cells at the gradient interface were collected, washed and resuspended (5×10⁵/ml) in {overscore (α)}MEM containing 10% FBS. In this study, we called these stromal cell-free, M-CSF-dependent, nonadherent cells as osteoclast precursors. These osteoclast precursors were added to 96-well plates (100 μl/well) containing plastic coverslips. Each well received further 100 μl of medium containing M-CSF (30 ng/ml), RANKL (30 ng/ml) without or with various concentrations of purified compound. Cultures were fed every 2-3 days and after incubation for 6 days osteoclast formation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining. The number of TRAP-positive multinucleated cells (MNCs) containing 3 or more nuclei was scored.

B. Characterization of Osteoclasts by TRAP Staining

Osteoclast formation was evaluated by quantification of TRAP-positive MNCs as described previously (Khapli et al. 2003). TRAP is preferentially expressed at high levels in osteoclast and is considered, especially in the mouse, to be an osteoclast marker. Cytochemical staining for TRAP is widely used for identifying the osteoclasts in vivo and in vitro. It is claimed to be specific for osteoclasts in bone. After incubation, cells on cover slips were washed in PBS, fixed in 10% formalin for 10 min and stained for acid phosphatase in the presence of 0.05 M sodium tartrate. The substrate used was napthol AS-BI phosphate. Only those cells that were strongly TRAP-positive (dark red) counted by light microscopy.

C. In Vitro Bone Resorption Assay

Osteoclast has the ability to excavate authentic resorption lacunae in vivo and in vitro. Bone resorption is the unique function of the osteoclast and is therefore the most useful means of distinguishing it from other cell types. M-CSF-dependent, non-adherent bone marrow cells were incubated for 10 days on bovine cortical bone slices in the presence of M-CSF, RANKL with or without various concentrations of compounds. Bone slices were examined for resorption pits by reflected light microscopy as previously described (Wani et al. 1999).

BRIEF DESCRIPTION OF THE ACCOMPANYING PLATES

Plate 1: Effect of compound as given in example 3 on RANKL-induced osteoclast differentiation from haemopoietic precursors of monocytes/macrophage lineage. Mice osteoclast precursors were incubated in the presence of M-CSF and RANKL in the absence and presence of the compound. Photomicrographs showing TRAP-positive osteoclasts in the absence (Plate 1A) and presence (Plate 1B) of the compound. This compound significantly inhibited osteoclast formation.

Plate 2: Effect of compound as described in example 4 on RANKL-induced osteoclast differentiation from haemopoietic precursors of monocytes/macrophage lineage. Photomicrographs showing TRAP-positive osteoclasts induced by M-CSF and RANKL in the absence (Plate 2A) and presence (Plate 2B) of the compound. This compound showed no inhibitory effect on osteoclast differentiation. 

1. A method for inhibiting osteoclast formation in a subject in need thereof, comprising the step of administering a pharmaceutically effective amount of a compound of the general formula ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in the compound is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂, optionally with an additive, excipient, diluent or carrier.
 2. The method according to claim 1, for inhibiting formation of mononuclear TRAP-positive osteoclasts.
 3. The method according to claim 1, for inhibiting formation of multinuclear TRAP-positive osteoclasts.
 4. The method according to claim 1, wherein the pharmaceutically effective amount is 5 to 10 mg/kg of body weight.
 5. The method according to claim 1, comprising administering the compound for between 5 and 30 days.
 6. The method according to claim 1, comprising administering the compound for at least 30 days.
 7. The method according to claim 1, comprising administering the compound for at least 60 days.
 8. The method according to claim 1, comprising administering the compound for at least 90 days.
 9. The method according to claim 1, wherein the compound has the structure shown below and the formula ZOC—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₄ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


10. The method according to claim 1, wherein the compound has the structure shown below and the formula ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₆ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


11. The method according to claim 1, wherein the compound has the structure shown below and the formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₈ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


12. The method according to claim 9, wherein the compound is selected from the group consisting of: I. L-Aspartic acid, N-Sulfonic acid, II. L-Aspartic acid, 2β-sulfonic acid, III. L-Aspartic acid, 2β-sulfate, IV. L-aspartic acid, 3α-sulfonic acid, V. L-aspartic acid, 3α-sulfate, VI. L-aspartic acid, 3β-sulfonic acid, VII. L-aspartic acid, 3β-sulfate, VIII. 2α,3-dicarboxy, propane-1-sulfonic acid, IX. 2α,3-dicarboxy, propane-1-sulfate, X. 1α,2-carboxy ethane sulfonic acid, XI. 1α,2-carboxy ethane sulfate, XII. D-aspartic acid, N-sulfonic acid, XIII. 2β,3-carboxy, propane-1-sulfonic acid, XIV. 2β,3-carboxy, propane-1-sulfate, XV. 1β,2-carboxy ethane-1-sulfonic acid, XVI. 1β,2-carboxy ethane-1-sulfate, XVII. D-aspartic acid, 2α-sulfonic acid, XVIII. D-aspartic acid, 2α-sulfonic acid, XIX. D-Aspartic acid, 3α-sulfonic acid, XX. D-Aspartic acid, 3α-sulfate, XXI. D-Aspartic acid, 3β-sulfonic acid, XXII. D-aspartic acid, 3β-sulfate, XXIII. L-asparagine, N-sulfonic acid, XXIV. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid, XXV. 2α-carboxy, 3-carboxamido, propane-1-sulfate, XXVI. 1α-carboxy, 2-carboxamido, ethane sulfonic acid, XXVII. 1α-carboxy, 2-carboxamido, ethane sulfate, XXVIII. L-asparagine, 2β-sulfonic acid, XXIX. L-asparagine, 2β-sulfate, XXX. L-asparagine, 3α-sulfonic acid, XXXI. L-asparagine, 3α-sulfate, XXXII. L-asparagine, 3β-sulfonic acid, XXXIII. L-asparagine, 3β-sulfate, XXXIV. D-asparagine, N-sulfonic acid, XXXV. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid, XXXVI. 2β-carboxy, 3-carboxamido, propane-1-sulfate, XXXVII. 1β-carboxy, 2-carboxamido, ethane sulfonic acid, XXXVIII. 1β-carboxy, 2-carboxamido, ethane sulfate, XXXIX. D-asparagine, 2α-sulfonic acid, XL. D-asparagine, 2α-sulfate, XLI. D-asparagine, 3α-sulfonic acid, XLII. D-asparagine, 3α-sulfate, XLIII. D-asparagine, 3β-sulfonic acid, XLIV. D-asparagine, 3β-sulfate.
 13. The method according to claim 10, wherein the compound is selected from the group consisting of: I. L-glutamic acid, N-sulfonic acid, II. 2α,4-dicarboxy, butane-1-sulfonic acid, III. 2α, 4-dicarboxy, butane-1-sulfate, IV. 1α,3-dicarboxy, propane sulfonic acid, V. 1α,3-dicarboxy, propane sulfate, VI. 1β,3-dicarboxy, propane sulfate, VII. 1β,3-dicarboxy, propane sulfonic acid, VIII. L-glutamic acid, 2β-sulfonic acid, IX. L-glutamic acid, 2β-sulfate, X. L-glutamic acid, 3α-sulfonic acid, XI. L-glutamic acid, 3α-sulfate, XII. L-glutamic acid, 3β-sulfonic acid, XIII. L-glutamic acid, 3β-sulfate, XIV. L-glutamic acid, 4α-sulfonic acid, XV. L-glutamic acid, 4α-sulfate, XVI. L-glutamic acid, 4β-sulfonic acid, XVII. L-glutamic acid, 4β-sulfate, XVIII. D-glutamic acid, N-sulfonic acid, XIX. 2β,4-dicarboxy, butane-1-sulfonic acid, XX. 2β,4-dicarboxy, butane-1-sulfate, XXI. D-glutamic acid, 2α-sulfonic acid, XXII. D-glutamic acid, 2α-sulfate, XXIII. D-glutamic acid, 3α-sulfonic acid, XXIV. D-glutamic acid, 3α-sulfate, XXV. D-glutamic acid, 3β-sulfonic acid, XXVI. D-glutamic acid, 3β-sulfate, XXVII. D-glutamic acid, 4α-sulfonic acid, XXVIII. D-glutamic acid, 4α-sulfate, XXIX. D-glutamic acid, 4β-sulfonic acid, XXX. D-glutamic acid, 4β-sulfate, XXXI. L-glutamine, N-sulfonic acid, XXXII. L-glutamine, 2β-sulfonic acid, XXXIII. L-glutamine, 2β-sulfate, XXXIV. L-glutamine, 3α-sulfonic acid, XXXV. L-glutamine, 3α-sulfate, XXXVI. L-glutamine, 3β-sulfonic acid, XXXVII. L-glutamine, 3β-sulfate, XXXVIII. L-glutamine, 4α-sulfonic acid, XXXIX. L-glutamine, 4α-sulfate, XL. L-glutamine, 4β-sulfonic acid, XLI. L-glutamine, 4β-sulfate, XLII. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid, XLIII. 2α-carboxy, 4-carboxamido, butane-1-sulfate, XLIV. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid, XLV. 1α-carboxy, 3-carboxamido, propane-1-sulfate, XLVI. 1β-carboxy, 3-carboxamido, propane-1-sulfate, XLVII. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid, XLVIII. D-glutamine, N-sulfonic acid, XLIX. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid, L. 2β-carboxy, 4-carboxamido, butane-1-sulfate, LI. D-glutamine, 2α-sulfonic acid, LII. D-glutamine, 2α-sulfate, LIII. D-glutamine, 3α-sulfonic acid, LIV. D-glutamine, 3α-sulfate, LV. D-glutamine, 3β-sulfonic acid, LVI. D-glutamine, 3β-sulfate, LVII. D-glutamine, 4α-sulfonic acid, LVIII. D-glutamine, 4α-sulfate, LIX. D-glutamine, 4β-sulfonic acid, LX. D-glutamine, 4β-sulfate.
 14. The method according to claim 11, wherein the compound is selected from the group consisting of: I. L-homoglutamic acid, N-sulfonic acid, II. Pentane-2α,5-dicarboxy-1-sulfonic acid, III. Pentane-2α,5-dicarboxy-1-sulfate, IV. Butane-1α,4-dicarboxy-1-sulfonic acid, V. Butane-1α,4-dicarboxy-1-sulfate, VI. L-homoglutamic acid, 2β-sulfonic acid, VII. L-homoglutamic acid, 2β-sulfate, VIII. L-homoglutamic acid, 3α-sulfonic acid, IX. L-homoglutamic acid, 3α-sulfate, X. L-homoglutamic acid, 3β-sulfonic acid, XI. L-homoglutamic acid, 3β-sulfate, XII. L-homoglutamic acid, 4α-sulfonic acid, XIII. L-homoglutamic acid, 4α-sulfate, XIV. L-homoglutamic acid, 4β-sulfonic acid, XV. L-homoglutamic acid, 4β-sulfate, XVI. L-homoglutamic acid, 5α-sulfonic acid, XVII. L-homoglutamic acid, 5α-sulfate, XVIII. L-homoglutamic acid, 5β-sulfonic acid, XIX. L-homoglutamic acid, 5β-sulfate, XX. D-homoglutamic acid, N-sulfonic acid, XXI. Pentane-2β,5-dicarboxy-1-sulfonic acid, XXII. Pentane-2β,5-dicarboxy-1-sulfate, XXIII. Butane-1β,4-dicarboxy-1-sulfonic acid, XXIV. Butane-1β,4-dicarboxy-1-sulfate, XXV. D-homoglutamic acid, 2α-sulfonic acid, XXVI. D-homoglutamic acid, 2α-sulfate, XXVII. D-homoglutamic acid, 3α-sulfonic acid, XXVIII. D-homoglutamic acid, 3α-sulfate, XXIX. D-homoglutamic acid, 3β-sulfonic acid, XXX. D-homoglutamic acid, 3β-sulfate, XXXI. D-homoglutamic acid, 4α-sulfonic acid, XXXII. D-homoglutamic acid, 4α-sulfate, XXXIII. D-homoglutamic acid, 4β-sulfonic acid, XXXIV. D-homoglutamic acid, 4β-sulfate, XXXV. D-homoglutamic acid, 5α-sulfonic acid, XXXVI. D-homoglutamic acid, 5α-sulfate, XXXVII. D-homoglutamic acid, 5β-sulfonic acid, XXXVIII. D-homoglutamic acid, 5β-sulfate, XXXIX. L-homoglutamine, N-sulfonic acid, XL. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid, XYLI. Pentane-2α-carboxy, 5-carboxamido-1-sulfate, XLII. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid, XLIII. Butane-1α-carboxy, 4-carboxamido-1-sulfate, XLIV. L-homoglutamine, 2β-sulfonic acid, XLV. L-homoglutamine, 2β-sulfate, XLVI. L-homoglutamine, 3α-sulfonic acid, XLVII. L-homoglutamine, 3α-sulfate, XLVIII. L-homoglutamine, 3β-sulfonic acid, XLIX. L-homoglutamine, 3β-sulfate, L. L-homoglutamine, 4α-sulfonic acid, LI. L-homoglutamine, 4α-sulfate, LII. L-homoglutamine, 4β-sulfonic acid, LIII. L-homoglutamine, 4β-sulfate, LIV. L-homoglutamine, 5α-sulfonic acid, LV. L-homoglutamine, 5α-sulfate, LVI. L-homoglutamine, 5β-sulfonic acid, LVII. L-homoglutamine, 5β-sulfate, LVIII. D-homoglutamine, N-sulfonic acid, LIX. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid, LX. Pentane-2β-carboxy, 5-carboxamido-1-sulfate, LXI. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid, LXII. Butane-1β-carboxy, 4-carboxamido-1-sulfate, LXIII. D-homoglutamine, 2α-sulfonic acid, LXIV. D-homoglutamine, 2α-sulfate, LXV. D-homoglutamine, 3α-sulfonic acid, LXVI. D-homoglutamine, 3α-sulfate, LXVII. D-homoglutamine, 3β-sulfonic acid, LXVIII. D-homoglutamine, 3β-sulfate, LXIX. D-homoglutamine, 4α-sulfonic acid, LXX. D-homoglutamine, 4α-sulfate, LXXI. D-homoglutamine, 4β-sulfonic acid, LXXII. D-homoglutamine, 4β-sulfate, LXXIII. D-homoglutamine, 5α-sulfonic acid, LXXIV. D-homoglutamine, 5α-sulfate, LXXV. D-homoglutamine, 5β-sulfonic acid, LXXVI. D-homoglutamine, 5β-sulfate.
 15. A method for treating osteoclasts in a subject in need of such treatment, comprising the step of administering a pharmaceutically effective amount of a compound of the general formula ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in the compound is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂, optionally with an additive, excipient, diluent or carrier.
 16. The method according to claim 15, for treating mononuclear TRAP-positive osteoclasts.
 17. The method according to claim 15, for treating multinuclear TRAP-positive osteoclasts.
 18. The method according to claim 15, wherein the pharmaceutically effective amount is 5 to 10 mg/kg of body weight.
 19. The method according to claim 15, comprising administering the compound for between 5 and 30 days.
 20. The method according to claim 15, comprising administering the compound for at least 30 days.
 21. The method according to claim 15, comprising administering the compound for at least 60 days.
 22. The method according to claim 15, comprising administering the compound for at least 90 days.
 23. The method according to claim 15, wherein the compound has the structure shown below and the formula ZOC—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₄ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


24. The method according to claim 15, wherein the compound has the structure shown below and the formula ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₆ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


25. The method according to claim 15, wherein the compound has the structure shown below and the formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein one of R₁ to R₈ is selected from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂


26. The method according to claim 23, wherein the compound is selected from the group consisting of: I. L-Aspartic acid, N-Sulfonic acid, II. L-Aspartic acid, 2β-sulfonic acid, III. L-Aspartic acid, 2β-sulfate, IV. L-aspartic acid, 3α-sulfonic acid, V. L-aspartic acid, 3α-sulfate, VI. L-aspartic acid, 3β-sulfonic acid, VII. L-aspartic acid, 3β-sulfate, VIII. 2α, 3-dicarboxy, propane-1-sulfonic acid, IX. 2α,3-dicarboxy, propane-1-sulfate, X. 1α,2-carboxy ethane sulfonic acid, XI. 1α,2-carboxy ethane sulfate, XII. D-aspartic acid, N-sulfonic acid, XIII. 2β,3-carboxy, propane-1-sulfonic acid, XIV. 2β,3-carboxy, propane-1-sulfate, XV. 1β,2-carboxy ethane-1-sulfonic acid, XVI. 1β,2-carboxy ethane-1-sulfate, XVII. D-aspartic acid, 2α-sulfonic acid, XVIII. D-aspartic acid, 2α-sulfonic acid, XIX. D-Aspartic acid, 3α-sulfonic acid, XX. D-Aspartic acid, 3α-sulfate, XXI. D-Aspartic acid, 3β-sulfonic acid, XXII. D-aspartic acid, 3β-sulfate, XXIII. L-asparagine, N-sulfonic acid, XXIV. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid, XXV. 2α-carboxy, 3-carboxamido, propane-1-sulfate, XXVI. 1α-carboxy, 2-carboxamido, ethane sulfonic acid, XXVII. 1α-carboxy, 2-carboxamido, ethane sulfate, XXVIII. L-asparagine, 2β-sulfonic acid, XXIX. L-asparagine, 2β-sulfate, XXX. L-asparagine, 3α-sulfonic acid, XXXI. L-asparagine, 3α-sulfate, XXXII. L-asparagine, 3β-sulfonic acid, XXXIII. L-asparagine, 3β-sulfate, XXXIV. D-asparagine, N-sulfonic acid, XXXV. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid, XXXVI. 2β-carboxy, 3-carboxamido, propane-1-sulfate, XXXVII. 1β-carboxy, 2-carboxamido, ethane sulfonic acid, XXXVIII. 1β-carboxy, 2-carboxamido, ethane sulfate, XXXIX. D-asparagine, 2α-sulfonic acid, XL. D-asparagine, 2α-sulfate, XLI. D-asparagine, 3α-sulfonic acid, XLII. D-asparagine, 3α-sulfate, XLIII. D-asparagine, 3β-sulfonic acid, XLIV. D-asparagine, 3β-sulfate.
 27. The method according to claim 24, wherein the compound is selected from the group consisting of: I. L-glutamic acid, N-sulfonic acid, II. 2α,4-dicarboxy, butane-1-sulfonic acid, III. 2α,4-dicarboxy, butane-1-sulfate, IV. 1α,3-dicarboxy, propane sulfonic acid, V. 1α,3-dicarboxy, propane sulfate, VI. 1β,3-dicarboxy, propane sulfate, VII. 1β,3-dicarboxy, propane sulfonic acid, VIII. L-glutamic acid, 2β-sulfonic acid, IX. L-glutamic acid, 2β-sulfate, X. L-glutamic acid, 3α-sulfonic acid, XI. L-glutamic acid, 3α-sulfate, XII. L-glutamic acid, 3β-sulfonic acid, XIII. L-glutamic acid, 3β-sulfate, XIV. L-glutamic acid, 4α-sulfonic acid, XV. L-glutamic acid, 4α-sulfate, XVI. L-glutamic acid, 4β-sulfonic acid, XVII. L-glutamic acid, 4β-sulfate, XVIII. D-glutamic acid, N-sulfonic acid, XIX. 2β,4-dicarboxy, butane-1-sulfonic acid, XX. 2β,4-dicarboxy, butane-1-sulfate, XXI. D-glutamic acid, 2α-sulfonic acid, XXII. D-glutamic acid, 2α-sulfate, XXIII. D-glutamic acid, 3α-sulfonic acid, XXIV. D-glutamic acid, 3α-sulfate, XXV. D-glutamic acid, 3β-sulfonic acid, XXVI. D-glutamic acid, 3β-sulfate, XXVII. D-glutamic acid, 4α-sulfonic acid, XXVIII. D-glutamic acid, 4α-sulfate, XXIX. D-glutamic acid, 4β-sulfonic acid, XXX. D-glutamic acid, 4β-sulfate, XXXI. L-glutamine, N-sulfonic acid, XXXII. L-glutamine, 2β-sulfonic acid, XXXIII. L-glutamine, 2β-sulfate, XXXIV. L-glutamine, 3α-sulfonic acid, XXXV. L-glutamine, 3α-sulfate, XXXVI. L-glutamine, 3β-sulfonic acid, XXXVII. L-glutamine, 3β-sulfate, XXXVIII. L-glutamine, 4α-sulfonic acid, XXXIX. L-glutamine, 4α-sulfate, XL. L-glutamine, 4β-sulfonic acid, XLI. L-glutamine, 4β-sulfate, XLII. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid, XLIII. 2α-carboxy, 4-carboxamido, butane-1-sulfate, XLIV. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid, XLV. 1α-carboxy, 3-carboxamido, propane-1-sulfate, XLVI. 1β-carboxy, 3-carboxamido, propane-1-sulfate, XLVII. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid, XLVIII. D-glutamine, N-sulfonic acid, XLIX. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid, L. 2β-carboxy, 4-carboxamido, butane-1-sulfate, LI. D-glutamine, 2α-sulfonic acid, LII. D-glutamine, 2α-sulfate, LIII. D-glutamine, 3α-sulfonic acid, LIV. D-glutamine, 3α-sulfate, LV. D-glutamine, 3β-sulfonic acid, LVI. D-glutamine, 3β-sulfate, LVII. D-glutamine, 4α-sulfonic acid, LVIII. D-glutamine, 4α-sulfate, LIX. D-glutamine, 4β-sulfonic acid, LX. D-glutamine, 4β-sulfate.
 28. The method according to claim 25, wherein the compound is selected from the group consisting of: I. L-homoglutamic acid, N-sulfonic acid, II. Pentane-2α,5-dicarboxy-1-sulfonic acid, III. Pentane-2α,5-dicarboxy-1-sulfate, IV. Butane-1α,4-dicarboxy-1-sulfonic acid, V. Butane-1α,4-dicarboxy-1-sulfate, VI. L-homoglutamic acid, 2β-sulfonic acid, VII. L-homoglutamic acid, 2β-sulfate, VIII. L-homoglutamic acid, 3α-sulfonic acid, IX. L-homoglutamic acid, 3α-sulfate, X. L-homoglutamic acid, 3β-sulfonic acid, XI. L-homoglutamic acid, 3β-sulfate, XII. L-homoglutamic acid, 4α-sulfonic acid, XIII. L-homoglutamic acid, 4α-sulfate, XIV. L-homoglutamic acid, 4β-sulfonic acid, XV. L-homoglutamic acid, 4β-sulfate, XVI. L-homoglutamic acid, 5α-sulfonic acid, XVII. L-homoglutamic acid, 5α-sulfate, XVIII. L-homoglutamic acid, 5β-sulfonic acid, XIX. L-homoglutamic acid, 5β-sulfate, XX. D-homoglutamic acid, N-sulfonic acid, XXI: Pentane-2α,5-dicarboxy-1-sulfonic acid, XXII. Pentane-2α,5-dicarboxy-1-sulfate, XXIII. Butane-1β,4-dicarboxy-1-sulfonic acid, XXIV. Butane-1β,4-dicarboxy-1-sulfate, XXV. D-homoglutamic acid, 2α-sulfonic acid, XXVI. D-homoglutamic acid, 2α-sulfate, XXVII. D-homoglutamic acid, 3α-sulfonic acid, XXVIII. D-homoglutamic acid, 3α-sulfate, XXIX. D-homoglutamic acid, 3β-sulfonic acid, XXX. D-homoglutamic acid, 3β-sulfate, XXXI. D-homoglutamic acid, 4α-sulfonic acid, XXXII. D-homoglutamic acid, 4α-sulfate, XXXIII. D-homoglutamic acid, 4β-sulfonic acid, XXXIV. D-homoglutamic acid, 4β-sulfate, XXXV. D-homoglutamic acid, 5α-sulfonic acid, XXXVI. D-homoglutamic acid, 5α-sulfate, XXXVII. D-homoglutamic acid, 5β-sulfonic acid, XXXVIII. D-homoglutamic acid, 5β-sulfate, XXXIX. L-homoglutamine, N-sulfonic acid, XL. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid, X LI. Pentane-2α-carboxy, 5-carboxamido-1-sulfate, XLII. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid, XLIII. Butane-1α-carboxy, 4-carboxamido-1-sulfate, XLIV. L-homoglutamine, 2β-sulfonic acid, XLV. L-homoglutamine, 2β-sulfate, XLVI. L-homoglutamine, 3α-sulfonic acid, XLVII. L-homoglutamine, 3α-sulfate, XLVIII. L-homoglutamine, 3β-sulfonic acid, XLIX. L-homoglutamine, 3β-sulfate, L. L-homoglutamine, 4α-sulfonic acid, LI. L-homoglutamine, 4α-sulfate, LII. L-homoglutamine, 4β-sulfonic acid, LIII. L-homoglutamine, 4β-sulfate, LIV. L-homoglutamine, 5α-sulfonic acid, LV. L-homoglutamine, 5α-sulfate, LVI. L-homoglutamine, 5β-sulfonic acid, LVII. L-homoglutamine, 5β-sulfate, LVIII. D-homoglutamine, N-sulfonic acid, LIX. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid, LX. Pentane-2β-carboxy, 5-carboxamido-1-sulfate, LXI. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid, LXII. Butane-1β-carboxy, 4-carboxamido-1-sulfate, LXIII. D-homoglutamine, 2α-sulfonic acid, LXIV. D-homoglutamine, 2α-sulfate, LXV. D-homoglutamine, 3α-sulfonic acid, LXVI. D-homoglutamine, 3α-sulfate, LXVII. D-homoglutamine, 3β-sulfonic acid, LXVIII. D-homoglutamine, 3β-sulfate, LXIX. D-homoglutamine, 4α-sulfonic acid, LXX. D-homoglutamine, 4α-sulfate, LXXI. D-homoglutamine, 4β-sulfonic acid, LXXII. D-homoglutamine, 4β-sulfate, LXXIII. D-homoglutamine, 5α-sulfonic acid, LXXIV. D-homoglutamine, 5α-sulfate, LXXV. D-homoglutamine, 5β-sulfonic acid, LXXVI. D-homoglutamine, 5β-sulfate. 